Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 53.1 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.101 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.121 mmol) to afford the desired product (28 mg, 53%) as a yellow glass: 1H NMR (300 MHz, CD3OD) δ 9.39 (s, 0.5H), 9.28 (s, 0.5H), 8.44 (d, J=2.2 Hz, 1H), 8.30-8.21 (m, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.40-7.17 (m, 2H), 4.96 (s, 1H), 3.99 (d, J=2.5 Hz, 3H), 3.72-3.52 (m, 1H), 3.43-3.18 (m, 3H), 2.98-2.81 (m, 1H), 2.59-1.75 (m, 9H), 1.48-1.34 (m, 6H), 1.31-1.13 (m, 4H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC>99% (AUC), tR=7.67 min.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH2:12][CH2:11][CH:10]([C:14]([O:16]C)=[O:15])[CH2:9][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([N:5]1[C:13]2[CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCc2c(c(-c3ccncc3)nn2C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(-c2ccncc2)c2c1CCC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 1-tert-butyl-3-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (1.6 g, 5 mmol) in THF (20 mL) was added LiOH (1 M, 10 mL, 10 mmol) and the reaction was stirred at room temperature for overnight. After removal of THF, HCl (1 N) was added until pH 4 to 5. The product precipitated as white solid and was collected by filtration (1.2 g). LC-MS found 300.2 (M+H)
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:14]([O:13][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A suspension of 3-tert-butyl-2-hydroxybenzaldehyde (11.3 g, 63.5 mmol, 1.0 equiv), benzyl bromide (10.8 g, 7.5 mL, 63.5 mmol, 1.0 equiv), powdered K2CO3 (17.5 g, 127 mmol, 2.0 equiv) and MeCN (300 mL) was refluxed for 4 hr. The pale green suspension was cooled to room temperature, filtered, washing the solids with EtOAc (150 mL). The filtrate was concentrated under reduced pressure to give a pale green oil. The crude product was chromatographed on silica gel (175 g) packed in heptanes (loaded as a solution in heptanes). The column was eluted with heptanes (1 L), 2% MTBE/heptanes (1 L) and 3% MTBE/heptanes (1.5 L). Product fractions were concentrated under reduced pressure to give 14.6 g (86%) of 21 as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 5-chloro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 352.2 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([C@H:25]([CH3:28])[CH2:26][CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C@@H:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH2:26][CH3:27]
Reactant: CC[C@@H](C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Trichloromethyl chloroformate (5.4 g, 27.3 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-3-methylpentan-1-ol 13 (4.97 g of 60%, 11.1 mmol) and triethylamine (5.3 g, 52.0 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 3 h at 0° C., then allowed to warm to room temperature for 18 h. The mixture was then washed with HCl (3×100 ml) and water (2×100 ml) and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 14 (2.7 g, 83%) as a white amorphous solid. m.p. 221–223° C. [α]D25=−243.9° (c, 4.33 in CHCl3). δH 0.41 (3H, t, J=7.2 Hz, CH3), 0.80 (3H, d, J=6.9 Hz, CH3), 0.80–0.96 (1H, m, CH2), 1.18–1.32 (1H, m, CH—Me), 1.34–1.50 (1H, m, CH2), 4.27 (1H, d, J=3.6 Hz, CH—NH), 6.98 (1H, s, NH), 7.10–7.50 (10H, m, Ar—H). δC 11.3 (CH3—CH2), 17.2 (CH3—CH), 22.7 (CH2), 36.3 (CH—Me), 66.1 (CH—NH), 89.5 (C), 125.9, 126.5, 127.7, 128.0, 128.3, 128.6, 139.3, 144.0 (Ar), 159.1 (C═O). νmax (cm−1): 3281, 3162 (N—H), 3058 (Ar C—H), 2980, 2960, 2933, 2877 (methyl and methylene C—H), 1760, 1725 (C═O), 1493, 1448 (Ar C═C), 1243 (C—O). m/e 313 (MNH4+, 6%), 296 (MH+, 8%), 237 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:17]#[N:16])=[CH:19][CH:20]=1)=[O:13]
Reactant: COc1ccc(C(OC)C(=O)O)c(Cl)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(Cl)c1

Procedure:
(RS)-(2-Chloro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(2-chloro-4-methoxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil. MS 345.2 ([M+H]+)
Reaction SMILES: N1C(C)=CC(C)=CC=1C.CS([Cl:14])(=O)=O.[Cl:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:25](=[O:38])[C:26]3[CH:35]=[C:34]([CH2:36]O)[S:33][C:27]=3[N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)=[O:23])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:25](=[O:38])[C:26]3[CH:35]=[C:34]([CH2:36][Cl:14])[S:33][C:27]=3[N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Reactant: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-N,N-Dimethylaminopyridine (80 mg), 2,4,6-collidine (1.39 mL), and methanesulfonyl chloride (0.81 mL) are added to a solution of N-(4-chlorobenzyl)-7-propyl-2-(hydroxymethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 12, 1.63 g) in anhydrous DMF (80 mL). The reaction mixture is stirred at room temperature for 24 h. The mixture is diluted with water (150 mL) and filtered. The resulting light yellow powder is recrystallized from acetonitrile and dried in a vacuum oven to afford 1.4 g of the title compound as a light yellow solid. Physical characteristics. Mp 186.5-188° C.; 1H NMR (300 Mhz,7 DMSO-6) δ 10.45, 8.75, 7.56, 7.39, 5.15, 4.54, 4.27, 1.85, 0.91. Anal. Found: C, 55.76; H, 4.59; N, 6.95; Cl, 16.88; S, 7.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C=O)=[C:13](C)[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: Cc1nc2n(c1C=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nccn1-2

Procedure:
A mixture of 1.0 g. of 8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1-carboxaldehyde (II) and 0.1 g. of tris(triphenylphosphine)rhodium chloride in 50 ml. of benzene is refluxed for about 6 hours. The mixture is then allowed to cool and filtered to remove the catalyst. The fitrate thus obtained is concentrated in vacuo to give 8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine, which is further purified by chromatography on silica gel and/or crystallization, m.p. 179°-180° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[C:40]([NH:43][CH:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)(=[O:42])[CH3:41]>>[C:40]([NH:43][CH:44]1[CH2:48][CH2:47][N:46]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:45]1)(=[O:42])[CH3:41]
Reactant: CC(=O)NC1CCNC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: CC(=O)NC1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)C1
Yield: 99.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 3-(acetylamino)pyrrolidine (23.1 mg) to obtain 2-[3-(acetylamino)pyrrolidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (92.6 mg, 99%).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[CH3:22][C:23](=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[C:23]([C:24]1[CH:25]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[S:12][CH:13]=[CH:14][C:10]=1[CH2:9][CH2:8]2)(=[O:26])[CH3:22]
Reactant: C#CC(C)=O
Reactant: Oc1c(-c2cccc(F)c2)sc2[n+]1CCc1ccsc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2

Procedure:
A solution of 0.303 g of 5,6-dihydro-3-hydroxy-2-(m-fluorophenyl)-thiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.145 ml of 3-butyn-2-one in 5 ml of toluene was heated under reflux for 1 hour. The solvent is evaporated in vacuo and the residue is chromatographed over silica gel with toluene/ethyl acetate (1:1). After recrystallization from ethanol, there was obtained 10-acetyl-4,5-dihydro-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizin-7-one of m.p. 109°-110°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.C([BH3-])#N.[Na+].[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH:29]=O)[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]>CO>[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: COC(=O)CCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NOCCO)c1cc(CN2CCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Methyl 4-amino-butyrate hydrochloride (commercially available, 48 mg, 0.312 mmol) and sodium cyanoborohydride (20 mg, 0.312 mmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (50 mg, 0.104 mmol) obtained in Step F of Example 1 in methanol (2.0 mL). The mixture was stirred at room temperature for 18 hours. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamide (Compound H-3, 26.8 mg, 47%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccccc1)c1ncc(CO[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccccc1)c1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
[5-(tert-Butyldimethylsiloxymethyl)pyrimidin-2-yl]phenylcarbamic acid tert-butyl ester (560 mg, 1.34 mmol) obtained in Step 5 was dissolved in THF (10 mL), and a 1.0 mol/L tetrabutylammonium fluoride-THF solution (4.02 mL, 4.02 mmol) was added to the solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to obtain (5-hydroxymethylpyrimidin-2-yl)phenylcarbamic acid tert-butyl ester (336 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)[C:13]([O-])=[O:14].[Tl+].C(O)(C(F)(F)F)=O.[Cl-].[Li+].[O-2].[Mg+2]>[Pd](Cl)Cl.CCOC(C)=O.C(Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[C:13](=[O:14])[O:10][CH2:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: OCc1cc(F)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C1OCc2cc(Br)cc(F)c21
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-5-fluorophenyl)methanol (360 mg, 1.8 mmol) and a stir bar was added added thallium trifluoroacetate (1.0 g, 1.8 mmol) and TFA (3.0 mL) at 0° C. The mixture was allowed to stir for 16 hours. LC showed no SM left at that point. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and concentrated twice to affect azeotropic removal of all TFA. After pumping the residue under high vacuum for 20 minutes, palladium chloride (31 mg, 0.18 mmol), lithium chloride (150 mg, 3.5 mmol), magnesium oxide (140 mg, 3.5 mmol), and MeOH (15 mL) were added to the flask. The mixture was treated under an atmosphere of CO for 2 hours. To this mixtue was added DCM and EtOAc to precipitate all the inorganic solids. The crude solution was filtered through a Celite® pad, and the filtrate was collected, adsorbed onto silica gel, and purified by silica gel chromatography. Removal of solvents gave rise to 5-bromo-7-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 231 [M+1]+;
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.[Cl-].[NH4+]>CS(C)=O>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (1.85 g, 10 mmol) in dimethylsulfoxide (10 mL) at room temperature, sodium hydride (440 mg of 60% dispersion in mineral oil, 11 mmol) is added in portions over a period of 20 min. After 30 min, 4-fluoronitrobenzene (1.06 mL, 10 mmol) is added and the mixture is heated by placing in an oil-bath maintained at 80° C. for 4 h. The reaction mixture is allowed to cool to room temperature, treated with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (250 mL). Organic extracts are combined, washed with brine (100 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo. The crude is purified chromatography over silica gel eluting with hexanes/ethyl acetate and the title compound is obtained as a light yellow solid, ESI m/z 307 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH:8]([Li])=[CH2:9]>>[CH:8]([CH:4]1[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH2:3]1)=[CH2:9]
Reactant: O=C1C=CCCO1
Reactant: [Li]C=C
Product: C=CC1CCOC(=O)C1

Procedure:
5,6-Dihydro-2H-pyran-2-one is treated with vinyllithium in the presence of a cuprous salt to obtain 4-ethenyl-tetrahydro-2H-pyran-2-one which is reacted with 3-bromopyridine under conditions of a Heck condensation (J. Org. Chem. 43, 2952 (1978), e.g. in the presence of Pd(OAc)2 and tri-o-tolylphosphine) to obtain 4-[2-(3-pyridyl)-ethenyl]-tetrahydro-2H-pyran-2-one. The lactone is reduced to the corresponding lactol, e.g. with diisobutyl aluminum hydride, which is condensed under Wittig conditions with e.g. methyl (triphenylphosphoranylidene)-acetate to obtain methyl 7-hydroxy-5-[2-(3-pyridyl)-ethenyl]-hept- 2-enoate. The two double bonds are then saturated using e.g. hydrogen in the presence of palladium on charcoal catalyst to obtain methyl 7-hydroxy-5-[2-(3-pyridyl)-ethyl]-heptanoate. The alcohol is converted to a reactive intermediate, e.g. the mesylate derivative, treated with e.g. sodium cyanide to obtain the nitrile which is then reduced to the methyl ester of the amine of formula XII wherein Het represents 3-pyridyl, A and M represent 1,3-propylene and B represents 1,2-ethylene.
Reaction SMILES: CO[C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2[C:21](OC)=[O:22].O.[NH2:26][NH2:27].C(OCC)(=O)C.O>CC(N(C)C)=O.[Cl-].[Na+].O>[N:26]1[NH:27][C:21](=[O:22])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[C:3]=1[C:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH2:13][CH2:12][C:11]=1[NH:10]3
Reactant: COC(=O)c1cccc2nc3c(c(OC)c12)-c1ccccc1CC3
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2c2ccccc2CC1
Temperature: 130 °C
Yield: 39 %

Procedure:
A mixture of methyl 12-methoxy-5,6-dihydrobenzo[a]acridine-11-carboxylate (20 mg, 0.06 mmol) and hydrazine hydrate (0.5 mL) in DMA (0.8 mL) was heated at 130° C. for 4 h. The reaction mixture was cooled, treated with ethyl acetate (0.5 mL), water (1 mL) and brine (1 mL). The resulting precipitate was collected by filtration, dissolved in a mixture of methanol:dichloromethane (1:8, 10 mL), dried over Na2SO4, filtered, concentrated, chromatographed on silica gel using gradint eluant of 0-3.2% methanol in dichloromethane to give the desired compound as a yellow solid (7 mg, 39%). 1H NMR (DMSO-d6) δ11.85 (s, 1H), 10.88 (s, 1H), 8.77-8.78 (m, 1H), 7.66-7.68 (m, 1H), 7.56-7.57 (m, 1H), 7.35-7.37 (m, 1H), 7.19-7.20 (m, 2H), 7.09-7.11 (m, 1H), 2.83-2.85 (m, 2H), 2.66-2.69 (m, 2H). MS (ESI) m/e [M+1]+288.
Reaction SMILES: [P:1]([O:39]CC1C=CC=CC=1)([O:31]CC1C=CC=CC=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[O:18])=[N:12]2)=[C:6]([C:27]([F:30])([F:29])[F:28])[CH:5]=1)=[O:2]>C(O)C.CO.CS(C)=O.[Pd]>[P:1]([OH:39])([OH:31])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[O:18])=[N:12]2)=[C:6]([C:27]([F:30])([F:29])[F:28])[CH:5]=1)=[O:2]
Reactant: O=C(Nc1ccn(Cc2ccc(OP(=O)(OCc3ccccc3)OCc3ccccc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccc(OP(=O)(O)O)cc2C(F)(F)F)n1)c1c(F)cccc1F

Procedure:
A solution of 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl bis(phenylmethyl) phosphate (for a preparation see Intermediate 58)(15.85 g, 24.1 mmol) in ethanol (200 ml) was hydrogenated using the H-cube midi (settings: 25° C., 15 bar, 10 ml/min flow rate) and 10% Pd/C CatCart as the catalyst. The solvent was evaporated in vacuo to give a white foam. The sample was loaded in methanol/DMSO and purified on reverse phase (C18) 1900 g using a 0-50% acetonitrile (+0.1% TFA)-water(+0.1% TFA) over 7 column volumes. The appropriate fractions were combined and the acetonitrile was removed in vacuo. The resulting suspension was filtered to give 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl dihydrogen phosphate (5.02 g). The filtrate was extracted using ethyl acetate (600 ml). The organic phase was dried over magnesium sulphate and evaporated in vacuo to give a further amount of 4-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]-3-(trifluoromethyl)phenyl dihydrogen phosphate as a white solid (2.39 g).