Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)C>[C:21]([O:11][CH2:10][CH2:9][NH:8][C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(NCCO)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-(4-nitroanilino)-1-ethanol (0.91 g) in dichloromethane (25 mL) at 0° C. is added triethylamine (1.8 mL), acetyl chloride (0.85 mL) and 4-dimethylaminopyridine (0.06 g). The reaction mixture is allowed to warm to room temperature over 3 hours. The reaction mixture is diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 0.61 g of 2-(4-Nitroanilino)ethyl acetate as a yellow solid To a Parr bottle containing 2-(4-nitroanilino)ethyl acetate (0.61 g) and ethyl acetate (10 mL) is added 10% palladium on carbon (0.05 g). The reaction mixture is shaken for 2 hours under 50 psi of hydrogen gas. The reaction mixture is filtered through Celite with ethyl acetate washes. The filtrate is concentrated under reduced pressure. The residue is treated with diethyl ethoxymethylenemalonate (0.60 mL) and heated to 135° C. under a flow of argon gas. After 1 hour the reaction is cooled to room temperature, adsorbed onto silica gel, and chromatographed on silica eluting with 60% to 80% ethyl acetate in heptane. The product-containing fractions are evaporated to give 0.45 g diethyl 2-[(4-{[2-(acetyloxy)ethyl]amino}-anilino)methylene]malonate as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])C.[OH-].[Li+]>>[C:39]([O:38][C:36]([N:25]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=1)[CH2:24][CH2:23][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:11][C:10]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OC(C)(C)C)c1

Procedure:
Prepared essentially as described in Example 9.1 Step B starting from 3-{2-[tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)-amino]-ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester and using lithium hydroxide to give the title compound.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:12][C:13]([Cl:19])([Cl:18])[C:14](=[NH:17])OC>>[Cl:12][C:13]([Cl:19])([Cl:18])[C:14]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])=[NH:17]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccccc1O
Product: N=C(NNC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 3.8 g (0.025 mole) salicoylhydrazine and 10 ml (14.3 g, 0.08 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The solid that formed was washed with petroleum ether and dried to give 7.5 g (100% Yield; mp 168°-169° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 99 %

Procedure:
2,4-Dichloroaniline (2.380 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (1.685 ml) under ice-cooling. After the mixture was stirred for 2 hours, 1N hydrochloric acid was added. The precipitated crystals were filtered, washed with water and then dried to give the title compound (3.4055 g, 99%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:21]([CH3:22])=[CH:20][C:19]([Br:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:7]2[N:6]3[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)cc2c1-n1c(Br)nnc1CN=C2c1ccccn1
Product: Cc1cc(Br)cc2c1-n1c(nnc1N1CCN(C)CC1)CN=C2c1ccccn1

Procedure:
In the manner given in Example 1, 1,8-dibromo-10-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-bromo-10-methyl-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[O:7][CH:6]=1)(=O)C>Cl.CO.O>[CH3:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5](=[O:4])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: CC(=O)Oc1coc2cc(C)ccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 6-methyl-1-benzofuran-3-yl acetate (3.8 g, 19.98 mmol) in HCl (4 mL, conc), methanol (160 mL), and water (40 mL) was heated under reflux for 1.5 h, the reaction mixture was cooled to room temperature, dissolved in water (200 mL) and filtered to give 6-methyl-2,3-dihydro-1-benzofuran-3-one as a white solid (2.5 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[CH:3][C:2]=1[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Temperature: 60 °C

Procedure:
A stirred mixture of 3′-bromo-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (26.6 g, 79.3 mmol), 3-nitrophenylboronic acid (21.2 g, 127 mmol), tri-o-tolylphosphine (2.51 g, 8.26 mmol), palladium (II) acetate (0.91 g, 4.05 mmol), potassium carbonate (21.9 g, 159 mmol) and water (100 mL) in dimethylformamide (400 mL) is heated at 60° C. for 2 h. The mixture is then treated with water (1000 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 10% ethyl acetate in cyclohexane) to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid, m.p. 106-108° C.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A stirring solution of methyl 2-(4-tert-butylbenzoyl-amino)benzoate (10.4 g, 33.4 mmol) and THF (200 mL) was treated with 1 M aqueous lithium hydroxide (40 mL) and methanol (80 mL). After stirring over night at room temperature, the mixture was treated with 1 M aqueous HCl (40 mL) and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (400 mL) and brine (100 mL). The organic phase was separated, then dried with MgSO4, filtered and concentrated in vacuo to give 9.69 g (98%) of a white powder.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:61]([O:63]C)=[O:62])[CH2:60][CH2:59][CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C:57]5([C:61]([OH:63])=[O:62])[CH2:58][CH2:59][CH2:60]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CCC2)C3)cc1)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
The compound of example 578 was prepared analogous to compound of example 98 by hydrolysis of compound of example 577.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:46])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:46])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown solid (510 mg, 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[S:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19])[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]4[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=4)[S:6][CH:7]=3)[CH2:25][CH2:24]2)[N:4]=1)=[O:22]
Reactant: COc1cc(C(=O)Nc2nc(CCl)cs2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(C(=O)Nc2nc(CN3CCN(Cc4csc(NC(=O)c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxybenzamido)-thiazole (140 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C([Li])CCC.Cl[C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:20]>C1COCC1>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[C:2]1([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[O:20])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1cnc(C2SCCCS2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C2(c3ncccn3)SCCCS2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,3-dithian-2-yl)pyrimidine (0.583 g, 2.94 mmol) in THF (50 ml) was added n-butyllithium (1.679 ml, 4.20 mmol, 2.5 M) by syringe at −78° C. The mixture was stirred at −78° C. for 0.5 h. Then tert-Butyl 4-(chlorocarbonyl)-piperidine-1-carboxylate (0.52 g, 2.1 mmol) in THF was added via syringe, and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with aqueous NH4Cl, and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The resulting crude material was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 354.08 [M+1−56]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)(C)C>[CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCOC(=O)NC=Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CCCCOC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
Analogously to the description in Example 2, 3.93 g (0.0135 mol) of 1-[p-(2-n-butoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane, on reaction with 1.22 ml (0.0142 mol) of isopropylamine in 50 ml of isopropanol, yield 1-[p-(2-n-butoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point of 125°-126° C. (from acetone-ether).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][CH:40]4[CH2:42][CH2:41]4)=[O:38])=[CH:32][C:31]=3[F:43])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=O)C.[Li+].[OH-]>C1COCC1.O>[CH:40]1([NH:39][C:37](=[O:38])[NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][C:26]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:21]=[C:20]([C:17]5[N:18]([CH3:19])[C:14]([CH2:13][N:8]([CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:7])[CH2:5][OH:4])=[CH:15][N:16]=5)[S:28][C:27]=34)=[C:31]([F:43])[CH:32]=2)[CH2:41][CH2:42]1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)C(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of 208 (104 mg, 0.170 mmol) in THF (18 mL) was added a solution of LiOH (32.6 mg, 1.362 mmol) in water (6 mL) and the mixture was stirred for 2 hr at room temperature before concentration. The residue was purified by Biotage (MeOH/DCM, 0-20%, SNAP 25 g cartridge) to give title compound 209 (40 mg, 0.070 mmol, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.55 (d, 1H, J=5.3 Hz), 7.94 (s, 1H), 7.75 (dd, 1H, J1=2.3 Hz, J2=13.5 Hz), 7.41 (t, 1H, J=9.0 Hz), 7.24-7.22 (m, 1H), 7.09 (s, 1H), 6.70 (d, 1H, J=5.5 Hz), 6.60 (m, 1H), 4.74 (s, 2H), 4.68-4.66 (m, 1H), 4.24 (d, J=5.7 Hz), 3.87 (s, 3H), 3.45 (m, 2H), 3.35 (s, 3H), 3.28 (m, 2H), 2.60-2.57 (m, 1H), 0.71-0.67 (m, 2H), 0.48-0.45 (m, 2H). MS: 569.6 (MH)+
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=O)[CH3:2].[S].[NH:10]1CCOC[CH2:11]1>[OH-].[Na+]>[CH:5]1[S:6][CH:7]=[C:8]2[C:4]=1[CH:1]=[CH:2][N:10]=[CH:11]2
Reactant: CC(=O)c1ccsc1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Product: c1cc2cscc2cn1

Procedure:
The thieno[3,4-c]pyridine compounds of formula I are prepared as follows: 3-Acetylthiopene 18 is reacted with sulfur in morpholine at reflux temperatures, and the resultant product is hydrolyzed in aqueous sodium hydroxide to give acid 19 (R12 =H) as a solid. Esterification in an alcoholic solvent, such as methanol or ethanol, using sulfuric acid catalysis yields the ester 19 (R11 =CH3 or C2H5). Ester 19 is acetylated with acetyl chloride using a metal halide catalyst, such as tin tetrachloride, to give 20. Reaction of 20 with concentrated ammonium hydroxide produces a mixture of amide 21 and thienopyridinol 22. Ring closure of 21 is effected by dissolution in trifluoroacetic acid to give 22; alternatively, the mixture of 21 and 22 obtained from the ammonolysis could be converted to 22 directly by the action of trifluoroacetic acid. Compound 23, wherein R2, R3 and R4 are as previously described, can be prepared as previously described in Schemes 1 and 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:21])=[O:20])[C:5]2=[O:22].[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CN(C=O)C.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([O:23][C:24]4[CH:29]=[N:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[CH:11][CH:10]=3)[C:5](=[O:22])[C:6]([C:19]([NH2:21])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: Cc1ccc(O)cn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3c(c2)c(=O)c(C(N)=O)cn3-c2ccc(F)cc2)cn1
Temperature: 150 °C
Yield: 55.6 %

Procedure:
Compound E (15 mg, 0.042 mmol, 1.0 eq), 5-hydroxy-2-methylpyridine (9.1 mg, 0.083 mmol, 2.0 eq), cesium carbonate (27 mg, 0.083 mmol, 2.0 eq), copper(I) iodide (0.79 mg, 0.0042 mmol, 0.10 eq) and N,N-dimethylglycine (1.3 mg, 0.013 mmol, 0.30 eq) were dissolved in DMF in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was filtered over Celite® and washed with 5% methanol in DCM. The organics were concentrated and purified using reverse phase chromatography to afford 9.1 mg (56%) of title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J=4.3 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.77-7.73 (m, 2H), 7.68 (d, J=3.0 Hz, 1H), 7.59 (d, J=4.3 Hz, 1H), 7.56-7.47 (m, 4H), 7.34 (d, J=8.5 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 2.49 (s, 3H); ES-MS [M+1]+: 390.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]([O:14]C)=[O:13])=[CH:5]2.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Cl)c(F)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(Cl)c(F)cc2[nH]1
Reaction time: 4 h
Yield: 97.6 %

Procedure:
Methyl 5-chloro-6-fluoroindole-2-carboxylate (461 mg) was dissolved in a mixed solvent of tetrahydrofuran (15 ml), methanol (10 ml) and water (10 ml), lithium hydroxide (283 mg) was added at room temperature, and the mixture was stirred for 4 hours. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid was added to the residue to weakly acidify it. The resultant powder was collected by filtration and dried to obtain the title compound (422 mg) as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12](O)=[O:13])[CH2:7]1.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:11]=2[C:12]([NH:27][C:28]2([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[CH2:30][CH2:29]2)=[O:13])[CH2:7]1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)cc1
Yield: 80.9 %

Procedure:
The title compound (D172) (60 mg) was prepared according to the experimental procedure described in Description 146 starting from 2-(3-(3-fluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D121) (50 mg, 0.14 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (31.95 mg, 0.14 mmol).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[C:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(=O)[CH3:8]>CO>[C:7](=[N:2][OH:3])([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: NO
Reactant: CC(=O)c1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.5 %

Procedure:
To a solution of 7.64 g. (110 mmole) of hydroxylamine hydrochloride in 150 ml. of methyl alcohol were added 5.94 g. (110 mmole) of sodium methylate and the mixture was stirred at room temperature for 10 minutes. A solution of 12.11 g. (110 mmoles) of 4-acetylpyridine in 50 ml. of methyl alcohol was added dropwise over 3 minutes and the reaction mixture was stirred at room temperature for 3 hours and at the reflux temperature for 2.5 hours. After the mixture had cooled, the precipitate of sodium chloride was separated by filtration and the filtrate was concentrated by evaporation to one-half of the original volume. The concentrate was diluted with 50 ml. of water and the solution concentrated to a volume of about 100 ml. This concentrate was chilled in an ice bath for 30 minutes and the precipitate of the oxime was separated by filtration in the cold. There were obtained 8.38 g. (61.5% yield) of 4-acetylpyridine oxime.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
To a solution of acid 402a (2.61g; 8.36 mmol; 1 eq), 1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36 mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64 ml; 33.4 mmol; 4 eq). After stirring overnight most of the DMF was removed under reduced pressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 was obtained in 70% (2.35 g). 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0,1H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49; found: 403.4.