Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.060 mmol), β-alanine (537 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 589.36 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:34][OH:35])([CH2:32][OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]([F:31])([F:30])[F:29])[CH:12]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]([F:29])([F:30])[F:31])[CH:12]=1)([CH2:32][OH:33])[CH2:34][OH:35]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 4-1 (490 mg) was dissolved in methylene chloride (7 ml), hydrogen chloride-containing dioxane (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 12 hr stirred for. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])#[N:2].[OH:15]O>[NH4+].[OH-]>[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([CH3:14])[C:3]=1[C:1]([NH2:2])=[O:15])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Nc1snc(C)c1C#N
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Product: CCCC(=O)Nc1snc(C)c1C(N)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N-(4-cyano-3-methyl-isothiazol-5-yl)-butyramide (method 5) (4.18 g, 20 mmol) in 30% aqueous NH4OH (250 mL), was added dropwise 100 mL of hydrogen peroxide at r.t. After the completion of the addition the reaction mixture was stirred at 60° C. overnight after which the TLC showed the complete disappearance of SM. The reaction mixture was cooled and extracted with chloroform (3×100 mL). The organic layer was dried (Na2SO4) and concentrated to get the pure 5-butyrylamino-3-methyl-isothiazole-4-carboxylic acid amide (2.9 g, 72%) as a white solid. 1H NMR (300 MHz) δ 1.03 (t, 3H), 1.79 (m, 2H), 2.54 (t, 3H), 2.69 (s, 3H), 5.97 (bs, 2H), 11.78 (bs, 1H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:32])[N:11]([CH:29]([CH3:31])[CH3:30])[C:12]=1[N:13]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH3:21])=[O:7])C>C1COCC1.CO>[Br:32][C:10]1[N:11]([CH:29]([CH3:31])[CH3:30])[C:12]([N:13]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1cc(Cl)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)cc1N(c1ccc(Cl)cc1)c1c(C(=O)O)nc(Br)n1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaOH (100 mL, 2 M aqueous solution, 200 mmol) was added to a solution of 2-bromo-5-[(4-chloro-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (step E2; 5.0 g, 9.6 mmol) in THF (100 mL) and MeOH (100 mL) at rt and reactants were stirred at rt for 2 h. THF and MeOH were evaporated, then the mixture was diluted in EtOAc/H2O and the pH was adjusted to 5 with diluted HCl. The aqueous layer was extracted once with EtOAc. The organic extract was dried (Na2SO4) and concentrated to afford an off-white foam; ESI-MS: 598.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 1.20 (d, J=18.38 Hz, 3 H) 1.44 (d, J=6.65 Hz, 3 H) 2.16 (s, 3 H) 4.97 (d, J=7.04 Hz, 1 H) 6.62 (dd, J=7.82, 1.95 Hz, 2 H) 6.78 (d, J=2.35 Hz, 1 H) 7.03 (d, J=7.82 Hz, 1 H) 7.27 (m, 2 H) 7.42 (m, J=8.60 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Li+].CC([N-]C(C)C)C.[O:19]1[C:23]2[C:24]([C:28]([CH3:33])([CH3:32])[CH2:29][CH:30]=[O:31])=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH:30]([OH:31])[CH2:29][C:28]([C:24]1[C:23]2[O:19][CH2:20][CH2:21][C:22]=2[CH:27]=[CH:26][CH:25]=1)([CH3:33])[CH3:32]
Reactant: CC(C)(CC=O)c1cccc2c1OCC2
Reactant: Cc1ccc(C#N)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(CC(O)Cc1ccc(C#N)cc1Cl)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 2-chloro-4-cyanotoluene (606 mg) in THF/DMPU (1:1, 8 mL) was treated dropwise with LDA (1.8 M in heptane/ethylbenzene/THF, 2.44 mL) at −78° C. After 30 minutes, 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanal (400 mg) was added in THF (1 mL) and the mixture was subsequently warmed to room temperature. After 1 hour, 5 mL of saturated ammonium chloride solution was added. The organic phase was separated and the aqueous layer was extracted with 20 mL of ethyl acetate. The combined organic phases were washed with three 10 mL portions of water and dried over magnesium sulfate. The solvent was removed. Flash chromatography (hexanes-EtOAc (gradient from 10:1 to 5:1)) of the residue yielded 460 mg (66%) of 1-(2-chloro-4-cyanophenyl)-4-(2,3-dihydrobenzofur-7-yl)-4-methyl-2-pentanol as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](O)=[O:31])[C:23]=3[N:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH2:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([NH:38][C:34]4[S:33][CH:37]=[CH:36][N:35]=4)=[O:31])[C:23]=3[N:22]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)CC1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccccc3OC3CCNCC3)nc12
Reaction time: 8 h

Procedure:
The same general amide coupling procedure outlined above was used, employing 2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 27 and 2-aminothiazole 4 as the starting materials. The resulting crude amide coupling product (0.2 mmol) was treated with 4 mL of 25% TFA in CH2Cl2 and allowed to stand at room temperature for 8 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC using aqueous acetonitrile that has buffered with 0.1% TFA to afford 2-(2-(piperidin-4-yloxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 428). MS (ESI) calcd for C22H21N5O2S: 419.14; found: 420 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol to give 63 mg (51%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.29 (br s, 1H, NH), 11.73 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.7 & 6.5 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.43 (m, 1H), 7.40 (s, 1H), 7.34 (t, J=9.05 Hz, 1H), 3.49 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1.[OH-].[Na+].[BrH:17]>O.[Cu]>[Br:17][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Br
Reactant: Nc1ccc2cn[nH]c2c1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2cn[nH]c2c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
Sodium nitrite (315 mg, 4.56 mmol) was added in 2 portions to an ice-cooled suspension of 6-aminoindazole (500 mg, 3.8 mmol) in water (0.4 mL) and hydrobromic acid (48%, 1.8 mL). The reaction mixture was stirred for 10 minutes longer than required for the brown gas to disappear. Copper powder (35 mg, 0.55 mmol) was then added and the mixture heated gently until nitrogen evolution began. The reaction mixture was then alternately heated and cooled to control the rate of reaction. When nitrogen evolution ceased, the reaction mixture was heated at 90° C. for 30 minutes, cooled to room temperature, neutralized with aqueous sodium hydroxide and the product extracted into ethyl acetate. The organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash chromatography on silica gel (20-40% ethyl acetate in hexane) yield the title product (119 mg, 16%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC(F)=CC=3)=NOC=2C)C=1)=O>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Agent: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Product: CCCCc1noc(C)c1COc1cc(C(=O)O)[nH]n1
Yield: 89.5 %

Procedure:
As described for example 10a, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (163 mg, 0.56 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester, was converted, to the title compound (140 mg, 90%) which was obtained as a white solid. MS: m/e=278.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[C@@H:13]([O:27][Si](C(C)(C)C)(C)C)[C@H:12]1[O:35][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[C@@H:13]([OH:27])[C@H:12]1[OH:35]
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of compound 31.3 (102 mg, 0.16 mmol) in THF (5 mL) was added a 1N solution of tetrabutylammonium fluoride in THF (0.15 mL, 0.5 mmol). The mixture was stirred at r.t. for 1 h and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 31.4 (38 mg, 59% yield). 1H NMR (300 MHz, CD3OD): δ 1.28 (m, 6H), 1.52 (s, 3H), 3.62 (m, 1H), 3.80 (m, 2H), 4.02 (m, 4H), 4.11 (m, 1H), 6.15 (d, 1H, J=7.1), 8.1 (s, 1H), 8.75 (s, 1H). LRMS (ESI) MH+ C15H24N5O7P requires 418.4. Found 417.9.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[C:11]([CH:12]=O)=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:3]([C:7]1[C:11]([CH2:12][NH:2][CH3:1])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NC)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 31.9 %

Procedure:
Methylamine (45.0 mg, 50 μl, 1.449 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100 mg, 0.248 mmol) and acetic acid (100 μl, 1.74 mmol) in DMF (1 mL). Sodium triacetoxyborohydride (527 mg, 2.484 mmol) was added and the reaction stirred for 17 h. The reaction was quenched with water (500 μl) and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title product (33 mg, 0.079 mmol, 32%).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18].C1(C)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)[CH3:18]
Reactant: CCNCCCN
Reactant: O=C1c2ccccc2CSc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCNCCCN=C1c2ccccc2CSc2ccccc21

Procedure:
9.1 g. of dibenzo[b,e]thiepin-11(6H)-one are mixed, while stirring, with 40 g. of N-ethyl-1,3-propanediamine and 250 ml. of absolute toluene and treated dropwise at 0° C. with 8.8 ml. of titanium tetrachloride. The reaction mixture is stirred at room temperature for 18 hours, then cooled and hydrolyzed with 250 ml. of water. The resulting suspension is filtered through diatomaceous earth and the aqueous phase is extracted with toluene. The combined toluene extracts are dried over sodium sulfate and evaporated under reduced pressure. Raw N-ethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine is obtained which can be used directly in the above reaction.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][C:6]#[N:7])#[N:2].[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13]>O1CCCC1>[C:1]([N:3]=[C:4]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])[CH2:5][C:6]#[N:7])#[N:2]
Reactant: CCOC(CC#N)=NC#N
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(CC#N)=NC#N

Procedure:
A solution of 4.00 g (0.0292 m) ethyl N,2-dicyanoacetimidate and 2.83 g (0.0292 m) diallylamine in 60 ml tetrahydrofuran is stirred at 0° C. for twelve hours. The reaction is concentrated and filtered through silica gel (2% MeOH/CH2Cl2 eluent). The organic phase is concentrated and the residue chromatographed (HPLC, 1"× 40" of 30-50 μ silica gel, 2% MeOH/CH2Cl2) to give product. A minor impurity (200 mg) crystallizes out from CH2Cl2 -C6H12. The residual oil (3.08 g, 56%) has nmr, ir, and mass spec which are consistent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[C:5]([CH3:11])[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:11])=[CH:6][CH:7]=1
Reactant: COc1nc(C)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1nc(C)ccc1CBr
Yield: 30.1 %

Procedure:
To a solution of (2-methoxy-6-methylpyridin-3-yl)methanol (4.7 g, 30.7 mmol) in dichloromethane (150 mL) was added triphenylphosphine (12.1 g, 46.0 mmol). The mixture was cooled in an ice bath with stirring under an atmosphere of nitrogen. Carbon tetrabromide (15.3 g; 46.0 mmol) was added and the mixture was stirred for 90 minutes. The mixture was concentrated under reduced pressure and purified using column chromatography on silica, eluting with dichloromethane/hexanes (1:1) to give 3-(bromomethyl)-2-methoxy-6-methylpyridine (2.0 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.O>[F:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Clc1ncc(OC2CC2)c2ccccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ncc(OC2CC2)c2ccccc12
Temperature: 145 °C
Yield: 37.6 %

Procedure:
To a solution of 1-chloro-4-cyclopropoxyisoquinolin (2.3 g, 10.47 mmol) in DMSO (20 ml) was added cesium fluoride (6.36 g, 41.9 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.8 g, 37.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.09-8.07 (m, 2H), 7.83 (s, 1H), 7.76-7.71 (m, 1H), 7.67-7.63 (m, 1H), 3.96-3.94 (m, 1H), 0.90-0.89 (m, 4H); 19F NMR: δ ppm −78.58 (1F); MS: MS m/z 204.2 (M++1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[CH2:10][C:9]([C:11]2[N:12]=[C:13]([SH:16])[S:14][CH:15]=2)=[CH:8][CH2:7][N:6]1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18].O(P(OC1C=CC=CC=1)O[C:32]1[C@H:38]([CH3:39])[C@H:37]2[N:34]([C:35](=[O:47])[C@@H:36]2[C@H:40]([O:42][Si](C)(C)C)[CH3:41])[C:33]=1[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])C1C=CC=CC=1.C(#N)C.Cl>C1COCC1.CN(C=O)C>[CH2:20]([O:19][C:17]([N:6]1[CH2:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([S:16][C:32]3[C@H:38]([CH3:39])[C@H:37]4[N:34]([C:35](=[O:47])[C@@H:36]4[C@H:40]([OH:42])[CH3:41])[C:33]=3[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])[S:14][CH:15]=2)[CH2:10][C@H:5]1[CH2:4][OH:3])=[O:18])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](CO)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Sodium hydride (60 w/w %, 13.3 mg, 0.33 mmol) was added at 0–5° C. to a solution of allyl (2S)-2-(hydroxymethyl)-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (purity 70%, 139 mg, 0.33 mmol) in a mixture of THF (11.0 ml) and DMF(0.5 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 1.27 g, 0.67 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the solution was adjusted to pH 3 at 0–5° C. with 1N hydrochloric acid. After the mixture was stirred for 30 minutes, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with thin layer chromatography (10% methanol in chloroform) to give allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (87 mg, 46%).
Reaction SMILES: [Cl:1][CH2:2]C(=O)CC1SC=CC=1.[S:11]1[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=O)[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2.S(Cl)(Cl)=O>>[S:11]1[CH:15]=[C:14]([CH2:16][C:17](=[O:19])[CH2:2][Cl:1])[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2
Reactant: O=C(CCl)Cc1cccs1
Reactant: O=C(O)Cc1csc2ccccc12
Solvent: O=S(Cl)Cl
Product: O=C(CCl)Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-(thiophen-2-yl)propan-2-one was followed. To prepare the acid chloride, 2-(benzo[b]thiophen-3-yl)acetic acid (1.00 g, 5.20 mmol) was added to 6 mL thionyl chloride in a 25 mL round-bottomed flask. The mixture was stirred overnight at room temperature, and the thionyl chloride then removed in vacuo and the residue azeotroped twice with toluene. The acid chloride was then reacted with diazomethane and HCl. The crude product was purified by flash chromatography over silica gel (2-30% ethyl acetate in hexanes) to give pure material (0.661 g, 56% yield): 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 2H) 4.14 (d, J=1.0 Hz, 2H) 7.36-7.44 (m, 3H) 7.67-7.71 (m, 1H) 7.87-7.90 (m, 1H).