Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C@@:14]3([C:27]4([CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28]4)[N:26]4[C@@H:21]([C:22](=[O:47])[O:23][C@@H:24]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C@H:25]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:20]3[C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=3[F:55])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([C@@H:20]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[F:55])[C@H:21]([C:22]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]4)=[O:47])[N:26]([C@H:25]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:24]([OH:23])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:27]43[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH2:32]4)[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21

Procedure:
Trans-4-aminocyclohexanol (167 mg, 1.45 mmol) was added to a tetrahydrofuran (10 ml) solution of the compound (194 mg, 0.29 mmol) obtained in Step 1 above and the resulting mixture was heated to reflux for 6 days. After cooling, saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1 (v/v)] to give 230 mg (100%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)[C:14]([N+:27]([O-])=O)=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1.[C:30](O)(=O)C.C(N)=N>[Pd].C(O)C>[CH:24]([O:23][C:21]1[NH:20][N:19]=[C:18]([N:17]2[C:15]3=[N:16][C:11]([NH:10][C@H:8]([C:5]4[N:4]=[CH:3][CH:2]=[CH:7][N:6]=4)[CH3:9])=[CH:12][CH:13]=[C:14]3[N:27]=[CH:30]2)[CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CC(=O)O
Agent: [Pd]
Agent: N=CN
Solvent: CCO
Product: CC(C)Oc1cc(-n2cnc3ccc(N[C@@H](C)c4ncccn4)nc32)n[nH]1
Reaction time: 5 h

Procedure:
The titled compound was prepared using a procedure similar to the one described for the synthesis of Example 6 using N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 20) as the starting material. The starting material (1.7 g) was dissolved into ethanol (10 mL). To the solution was added Pd—C (0.3 g, 10%). A hydrogen inlet was introduced into the reaction flask. The resulting mixture was stirred for 5 hours. Formamidine acetate (2 g) was added to the resulting mixture. The mixture was stirred at 85° C. for 4 hours. The resulting mixture was filtered, and the filtrate was concentrated. The resulting residue was separated by Silica gel column. The title compound was obtained (0.14 g) as a by-product. LCMS: 365 [M+1]. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 2H), 8.20 (s, 1H), 7.60 (d, 1H), 7.20 (s, 2H), 6.50 (d, 1H), 6.10 (br, 1H), 5.10 (s, 1H), 4.70 (m, 1H), 1.40 (d, 3H), 1.30 (d, 6H).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([C:1]([OH:8])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[CH2:13][CH2:14]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cl[Mg]C1CCCC1
Reactant: N#Cc1ccc(OCCCN2CCC(C(=O)c3ccccc3)CC2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccccc3)C3CCCC3)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
4-(3-(4-Benzoylpiperidin-1-yl)propoxy)benzonitrile (1.4 g, 4 mmol) was dissolved in dry THF (˜25 mL), heated to 60° C. and a solution of cyclopentylmagnesium chloride (4 mL, 2M) was added and the reaction stirred for 1 h. The reaction was quenched (sat. NH4Cl) and extracted into EtOAc (2×). The organic layers were dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (0-4% MeOH in CH2Cl2). The combined fractions were further purified by reverse phase chromatography to give 117 mg (7% yield) of analytically pure title compound: 1H NMR (400 MHz, CDCl3) δ 7.54 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=7.6 Hz), 7.31 (2H, t, J=7.6 Hz), 7.22 (1H, t, J=7.2 Hz), 6.89 (2H, d, J=8.8 Hz), 4.02 (2H, t, J=6 Hz), 3.12-3.00 (2H, m), 2.74-2.62 (3H, m), 2.09-1.95 (4H, m), 1.80-1.60 (4H, m), 1.58-1.40 (7H, m), 1.25-1.24 (1H, m), 1.11-1.09 (1H, m); LC-MS (>98%) m/z=419.3 [M+H]; HRMS=419.2701 [M+H], 100%, calculated for C27H35N2O2, 419.2699.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26][CH3:27])[CH:17]=1)=[CH:13][C:12]([O:28][CH3:29])=[C:11]([O:30][CH3:31])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:26][CH3:27])[CH:17]=1)=[CH:13][C:12]([O:28][CH3:29])=[C:11]([O:30][CH3:31])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(OC)c1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To a solution of 6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (55.6 mg) in dichloromethane (2 ml), titanium tetrachloride (TiCl4) (125 mg) was added at 0° C., followed by stirring at the same temperature for 6 hours. The reaction mixture was poured over water and extracted with chloroform. The chloroform layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform (3:2, v/v) to yield 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (24.5 mg, 48%) which was then recrystallized from ethyl acetate-hexane having a melting point of 176 to 178° C.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:35]2[CH:40]=[CH:39][C:38]([N:41]([CH3:43])[CH3:42])=[CH:37][CH:36]=2)([CH2:11][CH2:12][CH2:13][CH2:14][P:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=O)=O)=[CH:5][CH:4]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>CC1C=CC=CC=1C>[CH3:34][N:32]([CH3:33])[C:29]1[CH:30]=[CH:31][C:26]([P:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=2)[CH2:14][CH2:13][CH2:12][CH2:11][P:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:44])=[CH:4][CH:5]=2)[C:35]2[CH:40]=[CH:39][C:38]([N:41]([CH3:42])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:28]=1
Reactant: CN(C)c1ccc(P(=O)(CCCCP(=O)(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: C[SiH](Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: CN(C)c1ccc(P(CCCCP(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
6.1 g (10 mmol) of 1,4-bis[bis(4-dimethylaminophenyl)phosphinyl]butane and 9.3 g (50 mmol) of tri-n-butylamine are initially charged in 30 ml of o-xylene in an argon atmosphere. 5.75 g (50 mmol) of methyldichlorosilane are slowly added dropwise with the reaction mixture warming up to 50° C. It is subsequently heated to 100° C. and stirred for 4 hours, then heated to 145° C. and stirred for 16 hours. Cooling the clear solution results in formation of colorless crystals which are filtered off and washed with 10 ml of degassed o-xylene. Drying in a high vacuum gives 5.5 g of colorless crystals, corresponding to a yield of 95%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[NH:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(I)[nH]c2CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(I)n(COCC[Si](C)(C)C)c2CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
To a solution of 2-iodo-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 28, 2.2 g, 6.06 mmol) in THF (35 mL) was added NaH (60% in paraffin oil, 254 mg, 6.36 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C. and SEM-Cl (1.13 mL, 6.36 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 0° C. and quenched carefully with water (100 mL). The resulting solution was extracted with EtOAc (2×100 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 100 g) eluting with 40% EtOAc in DCM to give the title compound (2.34 g) in a 78% yield.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reaction time: 3 h
Yield: 93.4 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl] benzoic acid methyl ester (3 g) was dissolved in methanol (47 ml) and then, aqueous 1N-sodium hydroxide (16 ml) was added slowly. The solution was stirred at 20~25° C. for 3 hours. 2N-HCl was added slowly to the mixture for neutralization (pH=~5) and then, the crystalline powder was precipitated. The crystalline powder was filtered, washed with water and methanol and dried to give 2.7 g (yield: 93%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: COc1ccccc1C(=O)CBr
Product: COc1ccccc1C(=O)COC(=O)CCNC(=O)OC(C)(C)C

Procedure:
The product was obtained starting from 3-(tert-butoxycarbonylamino)propanoic acid (400 mg, 2.11 mmol) and 2-bromo-1-(2-methoxyphenyl)ethanone (484 mg, 2.11 mmol) according to the method described in example 7, step 1 as black oil (786 mg, 2.1 mmol, 99.2%). MS: M=238.2 (M-Boc+H)+
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[O:10]=[C:11]([N:25]1[CH2:30][CH2:29][N:28]2[C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=[C:27]2[CH2:26]1)[CH:12]=[C:13]([NH2:24])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23].N>O.C1COCC1>[O:10]=[C:11]([N:25]1[CH2:30][CH2:29][N:28]2[C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=[C:27]2[CH2:26]1)[CH2:12][CH:13]([NH2:24])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -6.5 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask THF (75 mL) was taken. It was cooled to −8 to −5° C. and NaBH4 (1.87 g) was added. After that trifluoroacetic acid (11.3 g) was added dropwise at −15 to −5° C. over a period of 30-45 min. Separately, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added in small portions into the reaction mixture, keeping the temperature between −10 to −5° C. It was stirred for 1 h at −10 to −0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.9 g; % Y-97.6%; % Purity by HPLC-81.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][Cl:19])=[N:16][C:15]([C:20](Cl)=[O:21])=[N:14]1)=[O:5].[CH2:27]([NH2:29])[CH3:28]>O1CCOCC1>[CH2:27]([NH:29][C:20]([C:15]1[N:16]=[C:17]([CH2:18][Cl:19])[N:13]([C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=2[C:4](=[O:5])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[Cl:1])[N:14]=1)=[O:21])[CH3:28]
Reactant: O=C(Cl)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: CCN
Solvent: C1COCCO1
Product: CCNC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
The resulting crude 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carbonyl chloride is dissolved in 80 ml of dioxane, and to the solution is added dropwise at room temperature, in the course of 30 minutes, a solution of 1.98 g (0.044 mole) of ethylamine in 30 ml of dioxane. The ethylamine hydrochloride gradually precipitates out. The reaction mixture is concentrated in vacuo to dryness. Ice water and ether are added to the residue; the organic phase is separated and is washed successively with cold 1 N hydrochloric acid, with cold 0.1 N sodium hydroxide solution and with saturated sodium chloride solution. After drying, and concentration in vacuo, is obtained crude N-ethyl-1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11](C(O)=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([NH:39][CH2:38][C:37]([O:36][CH3:35])=[O:40])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 3 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (380 g, 1.52 mol) and diisopropylethylamine (DIPEA) (295 g, 2.28 mol). With agitation, the solution was cooled to 3° C. and charged with trimethylacetyl chloride (275.7 g, 2.29 mol) while maintaining a temperature of less than 11° C., The mixture was then agitated at ambient temperature for 2 hours. The mixture was then cooled to 10° C. and charged with a slurry of glycine methyl ester HCl (573.3 g, 4.57 mol) and THF (1689 g, 1900 mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambient temperature for 16 hours. The mixture was then charged with EtOH (1500 g, 1900 mL) and concentrated under reduced pressure to a reaction volume of about 5.8 L. The EtOH addition and concentration was repeated twice more. Water (3800 g) was then added and the mixture was agitated for 16 hours at ambient temperature. The resulting solid product was isolated by filtration and washed with a mixture of EtOH (300 g, 380 mL) and water (380 g), followed by water (3800 g), dried under reduced pressure for 18 hours at 50° C. to afforded 443 g (91% yield) of the desired product as an off-white solid. Purity by HPLC was 98.9%. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(F)ccc1C(=O)OC
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of methyl 2-bromo-4-fluorobenzoate (1 g, 4.29 mmol), allyltributylstannane (1.464 mL, 4.72 mmol), lithium chloride (0.364 g, 8.58 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.151 g, 0.215 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-fluorobenzoate (330 mg, 1.699 mmol, 39.6% yield) as an white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=8.6, 6.1 Hz, 1H), 7.09-6.87 (m, 2H), 6.01 (ddt, J=16.9, 10.3, 6.6 Hz, 1H), 5.19-4.96 (m, 2H), 3.90 (s, 3H), 3.80 (d, J=6.6 Hz, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([N:15]([CH3:39])[C:16]([N:18]([C@@H:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:22][C@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.C(N(CC)CC)C.[C:49]([Cl:52])(=[O:51])[CH3:50]>C(#N)C.C(OCC)(=O)C>[ClH:52].[C:49]([N:29]1[CH2:30][CH2:31][CH:26]([N:23]2[CH2:24][CH2:25][C@@H:20]([N:18]([CH3:19])[C:16]([N:15]([C:7]3[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:5]([C:4]([F:3])([F:40])[F:41])[CH:6]=3)[CH3:39])=[O:17])[C@H:21]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:22]2)[CH2:27][CH2:28]1)(=[O:51])[CH3:50]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)N(C)[C@@H]1CCN(C2CCNCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(N2CC[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of the compound (0.18 g) obtained in Example 81 and triethylamine (0.13 mL) in acetonitrile (6.0 mL) was added acetyl chloride (0.032 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 60→100% ethyl acetate/hexane) and treated with 2N hydrogen chloride/2-propanol to give the title compound (0.15 g, 80%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([I:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].Cl.C(N(CC)CC)C.[CH3:21][C:22]([O:25][C:26](ON=C(C1C=CC=CC=1)C#N)=[O:27])([CH3:24])[CH3:23]>O.O1CCCC1>[C:22]([O:25][C:26]([C:4]1[C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=[C:9]([I:12])[C:5]=1[C:6]([OH:8])=[O:7])=[O:27])([CH3:24])([CH3:23])[CH3:21]
Reactant: NCc1ccc(I)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)c1c(CN)ccc(I)c1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A suspension of 3-aminomethyl-6-iodobenzoic acid.circle-solid.HCl (8.0 g, 26 mmol) and triethylamine (8.7 g, 86 mmol) in 32 ml of H2O, was added to a solution of Boc-ON (8.0 g, 32 mmol) in 23 ml of tetrahydrofuran cooled to 0° C. The reaction mixture was stirred at room temperature for overnight, and the volatile compounds were removed by concentration under reduced pressure. The residue was diluted with H2O, washed with ether, acidified to pH 3 with 1N HCl, and extracted with ethyl acetate. The extracts were washed with H2O, brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This material was triturated from ether to provide the title compound (5.7 g, 59%) as a white powder; mp 182° C. (dec);
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([N:18]1[C:30]2[C:29]([S:31][CH3:32])=[C:28]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:41]=O.[Cl-].[NH4+]>O1CCCC1>[CH2:11]([N:18]1[C:30]2[C:29]([S:31][CH3:32])=[C:28]([CH:33]([OH:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=O
Reactant: CSc1c(CC(=O)OC(C)(C)C)ccc2c3ccccc3n(Cc3ccccc3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(C(O)C(=O)OC(C)(C)C)ccc2c3ccccc3n(Cc3ccccc3)c12

Procedure:
0.47 ml of a 1.0M solution of lithium hexamethyldisilazide in tetrahydrofuran was added, with ice-cooling, to a solution of 65 mg of tert-butyl (9-benzyl-1-methylthiocarbazol-2-yl)acetate, as obtained in Example 4, in 5 ml of tetrahydrofuran. The reaction mixture was then stirred for 1 hour in the presence of atmospheric oxygen. After this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 1.5 g of silica gel with a 3:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 43 mg of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].Cl[Sn]Cl>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1I
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1cc(N)ccc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
1-Iodo-2-methoxy-4-nitro-benzene (6.01 g, 21.54 mmol) in absolute ethanol (127 mL) was cooled with an ice bath and treated with SnCl2 (18.83 g, 99.31 mmol). The bath was removed and the mixture was stirred at room temperature for 4 h then poured into ice (300 mL), stirred and treated carefully with saturated aqueous sodium bicarbonate (250 mL) (pH 7-8). The solid was filtered with suction and the panel washed thoroughly with EtOAc (500 mL and 4×200 mL). The aqueous layer was separated, dried over sodium sulphate and evaporated. Purification of the crude by flash chromatography on silica gel (hexane/EtOAc 1/1) furnished the title compound (3.17 g, 59%).