Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28]>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:27]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][N:21]=2)=[O:28])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(Cl)c1cnccn1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1C(=O)O)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 2.0 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].C(NC(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 3-bromobenzoyl chloride (20 g, 91.1 mmol) in CH2Cl2 was added dropwise to a cold (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride (33.6 g, 319 mmol), diisopropylamine (98 mL, 551 mmol) in CH2Cl2 over 1 hour. The stirring continued at room temperature for 30 minutes then concentrated under vacuo. The resultant residue was dispersed in water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. This residue was purified on silica gel (ISCO) using hexanes/EtOAc (4/1) as the eluting solvent to give 3-bromo-N-methoxy-N-methylbenzamide as light yellow solid (20 g, 89% yield). m/e (M+H)+ 244. 1H NMR (400 MHz, DMSO-d6) δ ppm, 3.21 (s, 3H), 3.50 (s, 3H), 7.37-7.39, (m, 1H), 7.53-7.55 (m, 1H), 7.64-7.66 (m, 1H), 7.67-7.69 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:26]2[CH2:27][C:24]([OH:28])([CH3:23])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC1(O)CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1.38 g, 3.5 mmol) and 3-methyl-azetidin-3-ol (HCl salt, 519 mg, 4.2 mmol) were dissolved in iPrOH (3.5 mL). DIPEA (1.4 mL, 8 mmol) was added and the RM mixture was heated at 140° C. for 4 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M. HCl and brine. The organic phase was dried over Na2SO4 and the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc, from 50 to 100% EtOAc) to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.1 [M+H]+.
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][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[Cl:32][C:33]1[CH:38]=[C:37]([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][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NCC4CCN(C(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Yield: 43.4 %

Procedure:
Following general procedure F, tert-butyl 4-{[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]methyl}piperidine-1-carboxylate (55 mg, 0.110 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (46 mg, 0.165 mmol) to afford the desired product (27 mg, 43%) as a yellow solid: ESI MS m/z 567 [C31H36ClN3O5+H]+.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.42 g, 0.95 mmol) (from Example 53 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.33 g, 83%).
Reaction SMILES: [C:1](I)([F:4])([F:3])[F:2].[CH2:6]([N:13]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CS(C)=O.O>[CH2:6]([N:13]1[C:17]([C:1]([F:4])([F:3])[F:2])=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(F)cc1
Reactant: FC(F)(F)I
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Reaction time: 16 h

Procedure:
CF3I (10 g) gas was bubbled through a solution of 1-benzyl-3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (4.0 g, 12.94 mmol) in DMSO (40 mL) and FeSO4.7H2O (2.15 g, 7.76 mmol) at RT for 5 min. 30% Aqueous H2O2 (8.7 mL, 77.64 mmol) was then added at 0° C. and stirring was continued at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (1×100 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 60-120 mesh); it eluted with 10-12% EtOAc in petroleum ether to yield ACI-09 (1.7 g, 35%) as a white solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:14](=[O:24])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:35]=2[S:36][C:37]=1C(Cl)=O.ClC1C2C=CC(C(F)(F)F)=CC=2SC=1C(O)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:41][C:35]=2[S:36][C:37]=1[C:6]([N:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)[C:14](=[O:24])[CH2:13]2)[CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Reactant: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1Cl
Agent: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Temperature: 25 °C

Procedure:
A solution of intermediate 3c (prepared by procedures described in Example 4) in CH2Cl2 (2 mL) and TFA (0.5 mL) was stirred at room temperature for 1h. The solution was concentrated, and the residue was dissolved in CH2Cl2 (2.5 mL). To the resulting solution at 0° C. was added Et3N (0.11 mL, 0.79 mmol), followed by a solution of 3-chloro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride 5a (prepared from 3-chloro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid following the procedures described in Example 1, Step A) (0.14 mmol) in CH2Cl2 (1.5 mL). The reaction was slowly warmed up to room temperature in 2 h, and was then quenched with aq. NaHCO3. The mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave Cpd 8 as yellow solid (28 mg). MS 496 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([NH:19][N:20]=[C:21]([CH3:23])[CH3:22])=[O:18])=[N:9]2)=[N:6][CH:7]=1.[CH3:24][C:25](C)=[O:26].CCCCCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][C:10]([C:17]3[O:18][C:21]([CH3:23])([CH3:22])[N:20]([C:25](=[O:26])[CH3:24])[N:19]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(C)=NNC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Solvent: CCCCCC
Product: CC(=O)N1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)OC1(C)C
Temperature: 25 °C
Yield: 72 %

Procedure:
Step-2: 1-(5-Bromopyridin-2-yl)-N′-(propan-2-ylidene)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide: A solution of step-1 intermediate (1.0 g, 2.86 mmol) in acetone: hexane (1:1, 12 mL) was stirred at 70° C. for 3 h. The reaction was then cooled to room temperature and the solvent was evaporated under vacuum to afford 800 mg (72%) of the title compound as white solid. ESI-MS (m/z) 390, 392 [(MH)+, Br79,81].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:31])([F:33])[F:32])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)CC3)CC1

Procedure:
(R)-[3-[1-(4-Methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (0.08 g, 0.126 mmol) was dissolved in a solution of 3.1 N hydrochloric acid in 6 mL of ethyl acetate. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(4-methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one dihydrochloride 5 (90 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:14]=2)[CH:4]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[CH:31]1([NH:37][C:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:14]=3)[N:6]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCCC1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Solvent: C1COCCO1
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NC2CCCCC2)n1

Procedure:
A solution of EXAMPLE 1B (6.7 g, 15.1 mmol) and cyclohexanamine (6.90 mL, 60.3 mmol) in dioxane (165 mL) was heated at 100° C. overnight. The mixture was concentrated to afford the crude title compound which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccnc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1cc(CN2CCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The mixture of 2-chloro-pyridine-4-carbaldehyde and (300 mg, 2.12 mmol) and pyrrolidine (0.19 mL, 2.12 mmol) in DCM (10 mL) was treated with acetic acid (0.25 mL, 4.24 mmol). The mixture was stirred at room temperature for 10 minutes and NaBH(OAc)3 (899 mg, 4.24 mmol) was added. After overnight stirring, the reaction was washed with sat. NaHCO3 and extracted twice with DCM. The organic layers were combined and washed with water, brine, dried over sodium sulfate, filtrated and concentrated. The crude material was purified by column chromatography with MeOH/DCM (0-10%) and concentrated to give 120 mg of 2-chloro-4-pyrrolidin-1-ylmethyl-pyridine as a clear oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([NH2:11])[N:5]=1.[CH:12](Br)([CH3:14])[CH3:13].CO>CN(C=O)C>[CH:12]([O:10][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([NH2:11])[CH:7]=1)([CH3:14])[CH3:13]
Reactant: Nc1cc(O)nc(N)n1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(N)nc(N)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
634 mg of sodium hydride (60% in mineral oil, 17.12 mmol) are added in portions under an argon atmosphere to a vigorously stirred solution of 1.8 g (14.27 mmol) of 2,6-diaminopyrimidin-4-ol in 20 ml of DMF. After 30 min, 1.6 ml (17.12 mmol) of isopropyl bromide are added dropwise, and the solution is stirred at 40° C. for 12 h. Methanol (1 mol) is then added to the reaction mixture, which is directly purified by preparative HPLC. Combining the product fractions and removing the solvent result in 250 mg (12% of theory) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccc(Cl)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-chloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:5]1[S:1][C:2]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:4]=1
Reactant: CCOC(=O)COc1cccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(Cl)s1
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 2-thienyloxyacetate (1.1 g, 5.9 mmol) in acetic acid (15 mL) is added N-chlorosuccinimide (0.78 g, 5.9 mmol). The solution is stirred for 1.5 hour. After this time the solution is concentrated. The resulting oil is dissolved in ether and washed with 1N NaOH, water and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The title compound (1.26 g, 5.7 mmol) is obtained as an oil. 1H NMR (CDCl3, 300 MHz) δ6.52 (d, 1H), 6.06 (d, 1H), 4.60 (s, 2H), 4.24 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50 mg (0.13 mmol) of the compound from Example 32A, 39 mg (0.16 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 45 mg (0.54 mmol) of sodium bicarbonate are initially charged in 3 ml of dry DMF. The reaction mixture is stirred at RT for 12 h and then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[N:13][N:12]3[CH:24]=2)=[CH:5][C:4]=1[N+:25]([O-])=O)#[CH:2].CC(O)=O>C(O)C.O.[Fe]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[N:13][N:12]3[CH:24]=2)=[CH:5][C:4]=1[NH2:25])#[CH:2]
Reactant: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1N
Temperature: 80 °C
Yield: 72.3 %

Procedure:
To a solution of 2-(4-ethynyl-3-nitrophenyl)-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.050 g, 0.139 mmol) in ethanol (3 mL) and water (1 mL) containing AcOH (0.834 mmol) is added iron (0.038 g, 0.695 mmol). The mixture is stirred and heated at 80° C. for 2 hours, then concentrated under reduced pressure and sat. aqueous NaHCO3 (20 mL) is added. The mixture is extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.033 g, 73%) as a yellow solid: Rf 0.30 (1:1 EtOAc:hexanes); LCMS (m/z)=329.4 [M+H]+, tR=2.65 min. (compound same as Example 320)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25]([S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH3:27]>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Product: CCCS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino2-benzoyl-6-chloro-1H-indole-1-carboxylate (Example 1, step 2) and 1 -propanesulfonyl chloride.
Reaction SMILES: COC1C(OC)=C(OC)C=C(C)C=1C(C#N)=O.C([Mg:21][Cl:22])(C)C.Br[C:24]1[C:25]([O:32][CH3:33])=[N:26][CH:27]=[C:28]([Cl:31])[C:29]=1[CH3:30]>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:31][C:28]1[C:29]([CH3:30])=[C:24]([Mg:21][Cl:22])[C:25]([O:32][CH3:33])=[N:26][CH:27]=1
Reactant: CC(C)[Mg]Cl
Reactant: COc1ncc(Cl)c(C)c1Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: COc1cc(C)c(C(=O)C#N)c(OC)c1OC
Solvent: C1CCOC1
Product: COc1ncc(Cl)c(C)c1[Mg]Cl
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A solution having 1.9 g (8.0 mmol) of 2,3,4-trimethoxy-6-methylbenzoyl cyanide dissolved in 20 ml of tetrahydrofuran was cooled to −10° C., and 0.32 g (0.91 mmol) of iron(III) acetylacetonate were added, followed by stirring for 20 minutes. In another reactor, 4 ml of tetrahydrofuran was added to 4.1 ml (8.2 mmol) of an isopropylmagnesium chloride 2M tetrahydrofuran solution and the mixture was cooled to 0° C., and a solution having 1.0 g (4.2 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine dissolved in 5 ml of tetrahydrofuran was dropwise added, followed by stirring for 3 hours to form 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride. The pyridylmagnesium chloride solution thus prepared was dropwise added to the above prepared 2,3,4-trimethoxy-6-methylbenzoyl cyanide/iron mixed solution, followed by stirring for 3 hours. A 10% ammonium chloride aqueous solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.7 g (yield: 58%) of a desired product.
Reaction SMILES: CC1NC2C(C=1)=CC=CC=2.C(Cl)(=O)C(Cl)=[O:13].[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=[CH:22][CH:21]=2>C(OCC)C>[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[C:27](=[O:31])[C:28]([OH:13])=[O:29])=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(=O)Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cc1cc2ccccc2[nH]1
Solvent: CCOCC
Product: Cc1[nH]c2ccccc2c1C(=O)C(=O)O

Procedure:
A solution of 2-methylindole (32.8) in diethyl ether (300 ml.) was added at 30° to oxalyl chloride (35.0g.) diluted with diethyl ether (200 ml.). After stirring for 1 hour the precipitate of 2-methylindolylglyoxylyl chloride was collected by filtration and treated with methanol (300 ml.) to give the methyl ester of 2-methylindol-3-ylglyoxylic acid (30.0 g.) as a red powder m.p. 180°-183°.