Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[N:17]=2)=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:41][CH:42]=4)[CH:19]=3)[N:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3cccc(N)c3)cn3ccnc23)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3)cn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid ethyl ester (19) (44.2 mmol), triethylamine (66.4 mmol), and tetrahydrofuran (140 mL) is treated dropwise with a solution of 4-t-butylbenzoyl chloride (44.2 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at room temperature for 1 hr. Water (100 mL) is added and the mixture extracted with ethyl acetate (3×100 mL), the extracts are washed with water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and evaporated in vacuo. The residue is triturated with dichloromethane to give 4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoic acid ethyl ester (20) as a pale orange solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16]1.N1C=CC=CC=1>O>[CH2:16]1[C:17]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:19][CH:15]1[NH:14][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1CCC2(CCCCC2)C1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCC2(CCCCC2)C1)c1cnc2ccccc2n1
Yield: 84.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2-aminospiro(4.5)decane (150 mg, 0.79 mmol), pyridine (5 mL), and water (100 mL) yielding 206 mg (74%) of (236): rt=10.94 min.;
Reaction SMILES: C([O:8][C:9](=[O:74])[C@H:10]([CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][CH2:70]1)[NH:11][C:12](=[O:67])[C@H:13]([C:63]([CH3:66])([CH3:65])[CH3:64])[NH:14][C:15](=[O:62])[C@H:16]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])[NH:17][C:18](=[O:53])[C@H:19]([CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[NH:20][C:21](=[O:43])[C@H:22]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C1C=CC=CC=1>[Pd]>[C:30]([O:29][C:27]([CH2:26][CH2:25][C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:74])=[O:8])[CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][CH2:70]1)=[O:67])[C:63]([CH3:64])([CH3:65])[CH3:66])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])=[O:53])[CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:43])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:34])=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)O)C(C)(C)C
Yield: 97.8 %

Procedure:
A solution of 230 mg (0.223 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 10 ml of dimethylformamidewas hydrogenated over 25 mg of 10% palladium/carbon for 3 hours. The catalyst was removed by filtration, the filtrate was evaporated and the residue was triturated with diethyl ether to give 206 mg of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine as a white solid; MS: m/e 944 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20]N=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.Cl[C:26]1C=CN=C2NC=CC=12.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[CH:26]=[CH:20][N:19]=[C:18]4[NH:22][CH:23]=[CH:24][C:17]=34)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: c1cc(N2CCNC3(CC3)C2)c2cc[nH]c2n1

Procedure:
Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3cccc4[nH]ccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4[nH]ccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 15.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.050 g, 0.46 mmol), the title compound (0.009 g, 15%) was obtained.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]=2[F:37])[CH:21]=1>>[F:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:22]=1[C:20]1[CH:19]=[N:18][CH:17]=[C:16]([F:15])[CH:21]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cncc(F)c3)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cncc(F)c4)c3)cnc2n1
Yield: 21 %

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-fluoro-5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 65 to give 2-{3-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol as an off-white solid (30 mg, 21%). Bis-hydrochloride salt (from ethyl acetate: ethanol (1:1)): δH (360 MHz, d6-DMSO) 1.56 (6H, s), 7.67-7.73 (1H, m), 7.83-7.89 (2H, m), 8.05-8.07 (1H, m), 8.11-8.15 (1H, m), 8.51 (1H, s), 8.71 (1H, s), 8.80 (1H, s), 9.36 (1H, d, J 7).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Mg].C1(Br)CC1.[CH2:11]([C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][O:22][CH3:23])[CH3:12].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH:1]1([C:17]2[CH:16]=[CH:15][C:14]([O:20][CH2:21][O:22][CH3:23])=[C:13]([CH2:11][CH3:12])[CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCc1cc(I)ccc1OCOC
Reactant: Br[Mg]C1CC1
Agent: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(C2CC2)ccc1OCOC
Reaction time: 2 h

Procedure:
A solution of cyclopropylmagnesium bromide, freshly prepared from 2.49 g of magnesium and 13.3 g of cyclopropyl bromide in 40 ml of THF, was treated with 1.2 g of bistriphenylphosphine-nickel chloride and at 35–45° C. within 20 minutes with a solution of 20.8 g of 2-ethyl-4-iodo-1-methoxymethoxy-benzene in 40 ml of toluene. After stirring for 2 hours the reaction mixture was poured into aqueous ammonium chloride solution and extracted with ether. The organic phases were washed with water, saturated aqueous sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed over silica gel and gave 12.7 g of 4-cyclopropyl-2-ethyl-1-methoxymethoxy-benzene; MS (EI) m/z 206 (M), 176 (M−CH2O).
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:43][C:44](O)=[O:45])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:44](=[O:45])[CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCCC3)CC21
Yield: 77.8 %

Procedure:
By working according to the procedure of Example 1, starting from 0.62 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 0.40 g of 2-(1-pyrrolidinyl)phenylacetic acid, 0.70 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-(1-pyrrolidinyl)phenyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 236° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[S:50][C:51]2[CH:57]=[C:56]([O:58][S:59]([C:62]3[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][N:71]([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])=[CH:64][CH:63]=3)(=[O:61])=[O:60])[CH:55]=[CH:54][C:52]=2[N:53]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:48][C:49]2[S:50][C:51]3[CH:57]=[C:56]([O:58][S:59]([C:62]4[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][N:71]([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:73])[CH3:74])=[CH:64][CH:63]=4)(=[O:61])=[O:60])[CH:55]=[CH:54][C:52]=3[N:53]=2)[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CN(C(=O)OC(C)(C)C)C4)sc3c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.4 %

Procedure:
68 mg of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester, 256 mg of HBTU and 235 μl of DIEA are added to a solution of 4-(2-diisopropylamino-ethylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester (inter-mediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide. The solution obtained is stirred for 20 hours at room temperature. After addition of 50 ml of water, the reaction medium is extracted with 3 times 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 700 mg of crude oil. This oil is purified by elution in a 95/5 dichloromethane/methanol mixture at a flow rate of 10 ml/minute, on 20 g of silica, to give 39 mg of 3-{6-[4-(2-diisopropylaminoethylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:20]([O:22]C)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])=[C:5]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:30][C:31]([F:44])([F:43])[O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][C:33]([O:32][C:31]([F:44])([F:43])[F:30])=[CH:34][CH:35]=3)(=[O:41])=[O:40])=[CH:10][CH:9]=2)[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]1[C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C
Product: CC(C)C[C@H](NC(=O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc2n1C)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucinate and 4-trifluoromethoxybenzenesulfonyl chloride followed the procedure of Example 1 Step 3 as a brown solid: 1H NMR (DMSO-d6) δ 0.79 (d, J=6.3 Hz, 3H, 0.80 (d, J=6.3 Hz, 3H, 1.35-1.60 (m, 3H, 3.75 (s, 3H, 4.25-4.35 (m, 1H, 7.03 (dd, J=8.8, 2.0 Hz, 1H, 7.24 (d, J=1.4 Hz, 1H, 7.25-7.40 (m, 5H, 7.47 (d, J=8.9 Hz, 1H, 7.55 (d, J=7.9 Hz, 2H, 7.77 (d, J=7.9 Hz, 2H, 8.77 (d, J=7.9 Hz, 1H, 9.99 (s, 1H, 12.64 (br s, 1H; MS (ESI) m/z 604 (MH+), MS (ESI) m/z 602 [M-H]−; HRMS calcd for C29H29F3N3O6S: 604.1727; found (ESI+): 604.1716; Anal. calcd for C29H28F3N3O6S.0.4H2O: C, 57.02; H, 4.75; N, 6.96. Found: C, 56.70; H, 4.75; N, 6.94.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[N:3]1([CH2:32][CH2:31][CH2:30][CH2:29][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=3)=[CH:16][CH:15]=2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CCCCC(Br)CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCn3cncn3)cc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.296 g) in N,N-dimethylformamide (14 ml) was added 1,2,4-triazole (0.511 g) and 4-[4-(4-bromooctyloxy)phenyl]benzoic acid (1 g), and was stirred for 5 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(1,2,4-Triazol-1-yl)octyloxy]phenyl]benzoic acid (0.81 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19](O)([CH3:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:9]=2[O:10][CH:11]=1)[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH3:40][C:41]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19]([CH3:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:22][Si:44]([C:41]([CH3:43])([CH3:42])[CH3:40])([CH3:46])[CH3:45])[C:9]=2[O:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCc1coc2c1C(C)(O)c1ccccc1C2=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCc1coc2c(O[Si](C)(C)C(C)(C)C)c3ccccc3c(C)c12
Temperature: 0 °C
Yield: 369.9 %

Procedure:
A solution of 24.0 mg (0.076 mmol, 1.0 eq) of alcohol 16 in 5.0 mL of dry CH2Cl2 was stirred in a 5 mL round bottom flask at room temperature under argon. To this solution was added 36.6 μL of Et3SiH (0.229 mmol, 3.0 eq). The solution was then cooled to 0° C. in an ice water bath. After cooling, 28.0 μL (0.220 mmol, 2.9 eq) of BF3-Et2O was slowly added and the resulting solution was stirred until all the starting material was consumed by TLC (1:1 hexane:EtOAc, Rf=0.56). After alcohol 16 was completely consumed (˜15 minutes), 69.0 mg (0.456 mmol, 6.0 eq) of TBSCl and 31.0 mg (0.456 mmol, 6.0 eq) of imidazole were added at once and the ice water bath was removed. The solution was then stirred at room temperature until the reaction was complete by TLC (1:1 hexane:EtOAc, Rf=0.80). Upon completion (˜18 hours) the solution was diluted with CH2Cl2 and washed with a saturated aqueous NH4Cl solution. The aqueous layer was then extracted twice with CH2Cl2 and the combined organic fractions were dried over MgSO4 and concentrated. Silica gel chromatography (hexane/EtOAc) yielded 116 mg (69%) of 17 as a colorless solid, Rf 0.80 (1:1 hexane:EtOAc). Mp: 92.4-93.5° C. 1H-NMR (500 MHz, CDCl3): 8.31 (1H, m), 8.10 (1H, m), 7.47 (3H, m), 4.20 (2H, q, J=7.1 Hz), 3.29 (2H, t, J=7.6 Hz), 2.93 (3H, s), 2.78 (2H, t, J=7.7 Hz), 1.28 (3H, t, J=7.2 Hz), 1.15 (9H, s), 0.27 (6H, s). 13C-NMR (500 MHz, CDCl3): 172.93, 143.40, 143.25, 132.82, 130.16, 127.98, 125.74, 124.02, 123.87, 123.69, 122.69, 119.97, 118.53, 60.84, 34.56, 26.24, 21.79, 18.93, 14.45, 14.42, −3.86. IR (cm−1): 2960 (m), 2854 (w), 1740 (vs), 1630 (w), 1461 (m), 1389 (s), 1247 (m), 1117 (m), 985 (s), 828 (s), 752 (s). Anal. Calcd. for C24H32O4Si: C, 69.86; H, 7.82. Found: C, 70.18; H, 8.02.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.[CH2:40]([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:51][CH:50]=1)[NH2:47])[CH3:41].CCN(C(C)C)C(C)C>>[CH2:40]([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:53][CH:54]=1)[NH:47][C:7]([C:4]1[S:3][C:2]([OH:1])=[N:6][CH:5]=1)=[O:9])[CH3:41]
Reactant: O=C(O)c1cnc(O)s1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cnc(O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
2-Hydroxy-5-thiazolecarboxylic acid (9.0 mg, 62 μmol) and HATU (28.3 mg, 74 μmol) were stirred in DMA (0.5 mL, 5 mmol) for 10 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (22.7 mg, 62 μmol) and DIPEA (32.4 μL, 186 μmol) were added, and resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure and the residue was dissolved in 50% AcOH-water (1.5 mL), filtered, purified by reverse phase preparative HPLC, and lyophilized to yield the title compound (11.9 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C22H21ClFN3O5S, 494.09. found 494.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[NH2:14].Cl[CH2:16][CH:17](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:1][C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:14]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOC(CCl)OCC
Reactant: Nc1nnc(-c2ccccc2)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Brc1cc(-c2ccccc2)nn2ccnc12
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 4-bromo-6-phenylpyridazin-3-amine (1.2 g, 4.8 mmol), 2-chloro-1,1-diethoxyethane (0.884 g, 5.74 mmol), PTSA (1.09 g, 5.74 mmol) in isopropanol (25 mL) was heated to 80° C. for 40 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated aq. NaHCO3 solution (50 mL), extracted with dichloromethane (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 8-bromo-6-phenylimidazo[1,2-b]pyridazine (0.6 g, 46%) as a white solid. LC-MS: [M+H]+, 274.0, tR=1.541 min.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[Cl:33])[NH2:29]>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:29]([C:28]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:26]([Cl:25])[CH:27]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(-c2ccc(Cl)c(Cl)c2)c(=O)c2ccccc12)c1ccccc1
Temperature: 160 °C
Yield: 25.3 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and 3,4-dichloroaniline (250 mg) in acetonitrile (0.5 ml) were heated under microwave irradiation at 160° C. for 15 min. The reaction mixture was partitioned between 2M HCl (3 ml) and ethyl acetate (3 ml). The organic solution was absorbed on SiO2 (600 mg) and flash chromatographed on SiO2 (20 g) with gradient heptane-ethyl acetate to give 22 mg of the title compound as a white solid. LC-MS (m/z) 465.4 & 467.4 (MH+); tR=1.63.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[NH:39][CH2:38][CH2:37][NH:36][CH2:35]2)=[CH:30][CH:29]=1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:36]5[CH2:37][CH2:38][NH:39][CH:34]([C:31]6[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=6)[CH2:35]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Temperature: 90 °C
Yield: 70 %

Procedure:
A suspension of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) and (RS)-3-(4-methoxyphenyl)piperazine (2.3 g) in dimethyl sulphoxide (20 cc) is heated to a temperature in the region of 90° C. for 1 hour and a half. After cooling to approximately 20° C., the insoluble matter is drained, washed with water (3×15 cc) and recrystallized in a mixture of ethanol (100 cc) and dimethylformamide (25 cc). (RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.1 g) is obtained in the form of a yellow solid, m.p. 199° C.