Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23]1>>[OH:22][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CCCC(O)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxypentane gave 2-(3-(3-(2-hydroxypentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.93 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=6.0 Hz, 1H), 7.53-7.60 (m, 1H), 7.47-7.52 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.14-7.19 (m, 1H), 6.78-6.83 (m, 2H), 6.73 (d, J=8.2 Hz, 1H), 3.81 (d, J=4.8 Hz, 2H), 3.73-3.79 (m, 1H), 3.18-3.24 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.73-1.81 (m, 2H), 1.30-1.52 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH2:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:17][CH3:18])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[O:7])=[CH:4][C:3]=1[Br:25].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O-:44])=[O:43].[Na+]>>[NH2:1][C:2]1[C:14]([CH2:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:17][CH3:18])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:44][C:42](=[O:43])[CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:28]2[C:27]([Cl:26])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:33])=[O:7])=[CH:4][C:3]=1[Br:25]
Reactant: CCN(Cc1cc(C(=O)NCCCCl)cc(Br)c1N)C1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)NCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 3-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzamido]-n-propyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)c(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)c(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-difluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([OH:24])=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[Cl:16])=[O:6].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1B(O)O>>[S:25]1[C:26]([C:2]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:24])=[C:4]([CH:3]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[Cl:16])=[O:6])=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]1=2
Reactant: CC(C)(C)c1cc(Br)cc(C(=O)Nc2ccc(C#N)cc2Cl)c1O
Reactant: OB(O)c1cc2ccccc2s1
Product: CC(C)(C)c1cc(-c2cc3ccccc3s2)cc(C(=O)Nc2ccc(C#N)cc2Cl)c1O

Procedure:
The title compound was prepared from 3-bromo-5-tert-butyl-N-(2-chloro-4-cyanophenyl)-6-hydroxy-benzamide and benzothiophen-2-boronic acid
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([OH:16])=O)=[C:4]([O:17][CH3:18])[CH:3]=1.[N:19]1([CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:9][CH2:10]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([N:22]2[CH2:23][CH2:24][N:19]([CH:25]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28]3)[CH2:20][CH2:21]2)=[O:16])=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetic acid (110 mg, 0.41 mmol) and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (118 mg, 0.49 mmol) in DMF (15 mL) at RT, BOP (217 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (192 mg, 95% yield).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH2:1]([O:13][C:25](=[O:26])[CH2:24][N:23]([CH3:28])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CN(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
First, 1-dodecyl alcohol (2.98 g, 0.016 mol), triethylamine (1.62 g, 0.016 mol) and 4-(N,N-dimethylamino)pyridine (DMAP; 0.195 g, 0.0016 mol) were added to a solution of N,N-dimethylglycine hydrochloride (2.23 g, 0.016 mol) in dry N,N-dimethylformamide (DMF; 100 mL) under nitrogen atmosphere, and cooled to 0° C. Then, dicyclohexylcarbodiimide (DCC; 3.63 g, 0.0176 mol) in dry DMF (60 ml) was added thereto at 0° C. The reaction mixture was returned to room temperature and stirred for about one day, then DMF was evaporated under reduced pressure with a pump. The residue was dissolved using ether and aqueous saturated sodium bicarbonate solution, and the ether layer was collected and washed once with water and once with saturated saline, after which it was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resultant residue was separated by column chromatography (hexane:ethyl acetate:triethylamine=50:50:1) to give N,N-dimethylamino-acetate-1-dodecyl ester (C12-tertiary amine) (yield 48%, 2.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.[Br-].[C:15]([CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.O>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[CH:20][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 60.1 %

Procedure:
A stirred mixture of the compound of Step C, Example 2, (11.5 gm, 56.51 mmol), (carbethoxymethyl)triphenylphosphonium bromide (24.2 gm, 56.51 mmol) and triethylamine (50 mL) in benzene (200 mL), under N2, was heated to reflux for 1 hour. Water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, dried over magnesium sulfate and evaporated under reduce pressure to dryness. The residue was chromatographed on silica gel using hexane:EtOAc (15:5) mixture as eluent. The fractions were combined and evaporated under reduce pressure to obtain the title compound of Step D (9.3 gm, 60%) as a yellow solid; m.p. 86°-88° C.,
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:39][C:40]([CH3:51])=[C:41]([CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][C@H:46]3[CH3:50])[N:42]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[O:39][C:40]([CH3:51])=[C:41]([CH2:43][CH2:44][N:45]4[CH2:49][CH2:48][CH2:47][C@H:46]4[CH3:50])[N:42]=3)=[CH:34][CH:33]=2)=[CH:24][N:23]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ncc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cn1
Yield: 1.7 %

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.011 g, 0.05 mmol), anhydrous acetonitrile (8 mL), triphenylphosphine (0.051 g, 0.19 mmol), distilled water (2 mL), 2-methoxy-5-pyrimidineboronic acid (0.75 g, 4.87 mmol), 2-(4-bromophenyl)-4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Intermediate 73) (0.85 g, 2.43 mmol) and potassium carbonate (0.1.01 g, 7.30 mmol). Additionally recrystallise from acetonitrile/ethyl acetate to give the title compound as a cream coloured solid (0.016 g): MS (m/e): 379(M+1).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:86][CH2:87][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:89][CH2:90]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (250 mg, 0.345 mmol) was hydrolyzed by lithium hydroxide (73 mg, 1.726 mmol) in THF/methanol/water (5/2/1 ml) to yield crude 150 mg (76.14% yield) of the titled compound. MS: m/z=570.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[C:19]#[C:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[C:19]#[C:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(/C=C/C#CCc1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: NO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CC(C#CCc1ccccc1)NO)N1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-4-{[(1E)-5-phenyl-1-penten-3-ynyl]sulfonyl}piperazine (155 mg; 0.40 mmol) in THF (8 mL) was added hydroxylamine (0.71 mL; 12.1 mmol). The reaction mixture was heated at 60° C. for 1 h. It was then diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude (135 mg) by flash chromatography on silica gave the title compound (50 mg, 30% yield). HPLC, Rt: 3.84 min (purity: 94.5%). LC/MS, M+(ESI): 418.3, M−(ESI): 416.2. 1H NMR (CDCl3) δ: 7.22-7.31 (m, 5H), 7.01 (m, 4H), 4.33 (m, 1H), 3.62 (d, J=1.9 Hz, 2H), 3.53-3.60 (m, 5H), 3.20-3.27 (m, 5H). 1H NMR (CDCl3) δ: 7.30 (m, 5H), 6.95 (m, 4H), 6.32 (d, J=15.6 Hz, 1H), 6.07 (dt, J=16.1, 7.4 Hz, 1H), 3.90 (s, 2H), 3.78 (d, J=6.6 Hz, 2H), 3.22 (m, 4H), 2.91 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1=[O:25])[CH2:7]2)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C@@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C:9]1=[O:25])[CH2:7]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reaction time: 18 h

Procedure:
A mixture of 10% Pd/C (3 g) and (±)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-one from Step A (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the crude racemic compound. The enantiomers were resolved by HPLC, utilizing a Chiralcel OD column and eluting with MeOH. The first major peak to elute was (S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound, and the second major peak to elute was (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one. MS: m/z=382 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1ccccc1N
Yield: 73.4 %

Procedure:
Following General Procedure A, the title compound (1.7 g, 74%) was prepared from 2-aminobenzenethiol (1.1 g, 8.47 mmol), methyl 2-(bromomethyl)benzoate (1.9 g, 8.47 mmol), and K2CO3 (3.5 g, 25.4 mmol) in DMF (50 ml).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([OH:12])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.[Cl-].[NH4+]>[CH2:15]([O:12][C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3=[O:1])[CH2:10]1)[CH2:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1C2CC3CC1CC(OCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-oxoadamantan-1-ol (5.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (60%, 1.4 g) and benzyl bromide (3.9 ml) were added under ice cooling. The reaction mixture was then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride under ice cooling and extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure to give 5-benzyloxyadamantan-2-one (8g) as a colorless oil.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)[C:7](=[O:9])[N:8]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=4)[C:7](=[O:9])[N:8]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2ccc(=O)[nH]c2)c[nH]1
Solvent: c1ccncc1
Product: O=c1ccc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Yield: 13.1 %

Procedure:
2-methylsulfanyl-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (20 mg, 0.08 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (40 mg, 0.127 mmol, 1.58 eq) were heated in 300 μl of dry pyridine at 150° C. for 16 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/30% MeOH in DCM solvent system (gradient 5-100% of 30% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (5.4 mg, yield=11.7%, purity=90%). MS: [M+H]+=517.34. 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.81 (t, J=7.032 Hz, 2H), 3.23 (s, 2H), 3.43-3.53 (m, 2H), 6.24(d, J=9.45 Hz, 1H), 6.36 (br.s., 1H), 7.03-7.14 (m, 3H), 7.20-7.37 (m, 4H), 7.41 (d, J=2.55 Hz, 1H), 7.54 (s, 1H), 7.70 (d, J=8.82 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:8])[CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C=O)ccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (7-formyl-chroman-4-yl)-methyl-carbamic acid tert-butyl ester (554 mg, 1.90 mmol, 1.0 eq), piperidine (Aldrich, 195 mg, 2.28 mmol, 1.2 eq), NaBH(OAc)3 (Aldrich, 805 mg, 3.8 mmol, 2.0 eq) and glacial HOAc (J. T. Baker, 114 mg, 1.90 mmol, 1.0 eq) in ClCH2—CH2Cl (8 mL) was stirred at RT for 4 h. The reaction was quenched with saturated Na2CO3 (50 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-5% MeOH—CH2Cl2) afforded the title compound as colorless sticky solid. MS (ESI, pos. ion) m/z: 361 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[CH:36]=[CH:35][C:25]3[N:26]=[C:27]([NH:29][C:30]([CH:32]4[CH2:34][CH2:33]4)=[O:31])[S:28][C:24]=3[CH:23]=2)=[C:19]([F:39])[CH:18]=1.O>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(Cl)(=O)C(Cl)=O>[CH:32]1([C:30]([NH:29][C:27]2[S:28][C:24]3[CH:23]=[C:22]([O:21][C:20]4[CH:37]=[CH:38][C:17]([NH:16][C:13]([C:10]5([C:8]([NH:7][C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[O:9])[CH2:11][CH2:12]5)=[O:15])=[CH:18][C:19]=4[F:39])[CH:36]=[CH:35][C:25]=3[N:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (214 mg, 1.04 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (178 μL, 2.08 μmol) and N,N-dimethylformamide (2 drops) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in N,N-dimethylacetamide (5 mL) was added N-[6-(4-amino-2-fluorophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (275 mg, 0.80 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→20/80, NH silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate to give the title compound (241 mg, 57%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)[C:17]([N+:33]([O-:35])=[O:34])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:44]1(B(O)O)[CH2:46][CH2:45]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH:44]1([C:2]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[CH2:22][CH2:21]3)[C:17]([N+:33]([O-:35])=[O:34])=[CH:16][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[O:5])[CH2:46][CH2:45]1
Reactant: OB(O)C1CC1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 80 %

Procedure:
2-Chloro-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 1f (200.0 mg, 0.40 mmol, 100 mol %), potassium phosphate tribasic (169.8 mg, 0.80 mmol, 200 mol %), cyclopropylboronic acid (41.2 mg, 0.48 mmol, 120 mol %), tricyclohexylphosphine (11.2 mg, 0.04 mmol, 10 mol %), and palladium(II) acetate (4.5 mg, 0.02 mmol, 5 mol %) were combined in de-gassed toluene (4.0 ml) and 200 mL of water was added. The vessel was sealed and heated to 100° C. for 3 h and then the reaction was cooled and diluted with water and ethyl acetate. The suspension was filtered through a pad of Celite and the mixture was extracted twice with ethyl acetate and the combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography (dichloromethane to 10% methanol in dichloromethane) afforded 2-cyclopropyl-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 5a (161.0 mg; 0.32 mmol; 79.6%) as an amorphous yellow solid. LCMS (ESI) 506 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[CH3:17]>CN1C(=O)CCC1>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH2:12][O:13][CH3:14])=[CH:11][C:2]([NH:29][CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][C:21]4[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:19]([O:18][CH2:16][CH3:17])[CH:20]=4)[CH2:24][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COCc1cc(Cl)nc2cc(Cl)ccc12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3cc(COC)c4ccc(Cl)cc4n3)CC2)ccc1OC
Yield: 13.6 %

Procedure:
A solution of 2,7-dichloro-4-methoxymethyl-quinoline (36.3 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.5 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 9.6 mg (14%) of the title compound. MS (ISP): 470.4 [M+H]+.