Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH3:11])[NH:7][CH:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[N:7]([C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C@H:6]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CCC(C)NC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
(A mixture of two diastereomers and their enantiomers.) To 6-Methyl-2-phenyl-piperidine-3-carboxylic acid methyl ester (1.63 g, 7.0 mmol) in 20 mL of 10% aqueous NaHCO3 at 0° C. was added benzylchloroformate (1.25 g, 7.35 mmol). The mixture was stirred for 45 minutes at 0° C., and was then warmed to room temperature and stirred for an additional 30 minutes. The mixture was partitioned with ether, and the organic phase was dried over MgSO4 and concentrated. Silica gel chromatography (9:1 hexanes/EtOAc) gave 1.62 g (63%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.1–7.4 (comp, 20H, both diastereomers), 6.1 (br, 1H, minor diastereomer), 5.74 (d, J=3.6, 1H, major diastereomer), 5.05–5.26 (comp, 8H, both diastereomers), 4.67 (d, J=6.0 Hz, 1H, major diastereomer), 4.57 (m, 1H, minor diastereomer), 4.10–4.20 (m, 2H, major diastereomer), 3.70 (s, 3H, major diastereomer), 3.59 (s, 3H, major diastereomer), 3.29 (app dt, J=4.5, 9.4 Hz, 1H, major diastereomer), 2.85 (m, 1H, minor diastereomer), 2.27 (app dq, J=4.1, 13.7 Hz, minor diastereomer), 1.85–2.15 (comp, 4H, both diastereomers), 1.55–1.80 (comp, 3H, both diastereomers), 1.34 (d, J=6.8 Hz, 3H, major diastereomer), 0.37 (d, J=7.1 Hz, 3H, minor diastereomer); 13C NMR (100 MHz) δ 172.8, 140.0, 136.7, 128.5, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 127.2, 127.1, 127.0, 126.9, 126.4, 67.5, 66.9, 65.3, 56.4, 52.0, 47.5, 46.6, 44.3, 42.6, 30.2, 25.6, 22.1, 19.8, 17.2, 16.0; mass spectrum m/e calcd. for M+H=368.2. Found 368.2, 324.2 (base).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC.CO.C(=O)(O)[O-].[Na+]>O>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])[C:6]([OH:24])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1O

Procedure:
To a boiling solution of 23 g. (0.067 mol.) of N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester in 300 ml. of methanol was slowly added a solution of 23 g. of sodium bicarbonate in 300 ml. of water. During addition, the reaction mixture was kept under a nitrogen atmosphere and the methanol was allowed to distill from the mixture. When all the methanol had been distilled the mixture was cooled, adjusted to pH 7.0 with phosphoric acid and extracted with ethyl acetate. The aqueous phase was acidified to pH 4.0 and again extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].Br[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:18]([C:16]1[O:17][C:13]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: O=Cc1ccc(Br)o1
Reactant: N#Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(-c2ccc(C=O)o2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A suspension of 3-cyanoindole (0.14 g), 5-bromo-2-furaldehyde (0.18 g), and cesium carbonate (0.39 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature or 3 hours. This reaction mixture was heated at 50° C., stirred for 2 hours. After cooling to ambient, water was added to this reaction mixture. This mixture was extracted with ethyl acetate, and this organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.086 g).
Reaction SMILES: [Na].Br[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6]>C(O)C.O>[CH3:8][C:4]1([CH3:9])[CH:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6][C:5]1=[O:7]
Reactant: CC(=O)C(C)(C)C(Br)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1(C)C(=O)CC1c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
0.91 g (0.04 mol) of sodium is dissolved in 100 ml of ethanol and, at 20° C., 10.5 g (0.036 mol) of 1-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone in 20 ml of ethanol are added. The reaction mixture is stirred at 20° C. for about 15 hours, diluted with water and neutralized. It is extracted with methylene chloride, dried with sodium sulphate and the solvent is distilled off from the filtrate under waterpump vacuum. The residue is purified by distillation under high vacuum. 4.8 g (65% of theory) of 2,2-dimethyl-3-(4-chlorophenyl)cyclobutanone of boiling point 98° to 107° C./0.05 mbar are obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][N:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: Brc1nnc2n1CCNC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1CCn2c(Br)nnc2C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A suspension of 3-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (Preparation 154, 29 mg, 0.143 mmol), K2CO3 (23.7 mg, 0.171 mmol), dimethyl sulfate (14 uL, 0.143 mmol in THF (3 mL) was stirred at 80° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered and purified by elution through an SCX-2 column using 2M NH3/MeOH to give the title compound as yellow oil (16.5 mg, 53%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](C3C=CC(SC)=CC=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.[C:29](O)(=O)[CH3:30]>O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([S:7]([C:1]3[CH:6]=[CH:5][C:29]([CH3:30])=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 23.4 mmol) in glacial acetic acid (15 mL) was added 30% H2O2 solution (2.45 g, 72 mmol) and the resulting 2-phase mixture was heated at reflux for 30 min during which time it became a solid mass. The reaction mixture was cooled to ambient temperature and diluted with H2O and ethyl acetate and the solid was filtered off. The filtrate layers were separated and the organic phase was washed with saturated aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/ether and the resulting solid was combined with the solid obtained above and recrystallized from ethyl acetate to give 8.15 g of 1-phenylsulfonyl-3-(4-methylphenylsulfonyl)indole. mp 188.9°-189.7° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:23][NH:24][S:25](Cl)(=[O:27])=[O:26].[BH4-].[Na+]>N1C=CC=CC=1>[F:22][C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:25](=[O:27])(=[O:26])[N:24]2[CH3:23])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2ccc3cccnc3c2N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)cc1F
Yield: 58 %

Procedure:
In a similar fashion using route 27 general procedure 71, (8-amino-quinolin-7-yl)-(3-fluoro-4-methoxy-phenyl)-methanone (Intermediate 381) (200 mg, 0.6 mmol), N-methylsulfamyl chloride (Intermediate 213) (260 mg, 2.0 mmol), NaBH4 (76 mg, 2.0 mmol) and pyridine (2 ml) gave the title compound (130 mg, 52%) after purification by column chromatography with n-hexane/EtOAc (50:50) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]4)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Yield: 59.1 %

Procedure:
The title compound (1.57 g, 59% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4,7-dichloroquinoline (1.81 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 350 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](Cl)=[N:8][C:7]=1[O:16][CH2:17][CH:18]([F:20])[F:19]>C1COCC1>[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([NH:2][CH3:1])=[N:8][C:7]=1[O:16][CH2:17][CH:18]([F:20])[F:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(OCC(F)F)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
Methylamine (2 M in THF; 32.0 mL, 64.0 mmol) is added at 10° C. to 6-chloro-2-(2,2-difluoro-ethoxy)-5-nitro-nicotinic acid methyl ester (9.1 g, 30.7 mmol) in THF (50 mL). After 1 h at rt the reaction mixture is concentrated, treated with water and filtered. The filtercake is washed with water and dried to give the sub-title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][C:6]2[CH:5]=[N:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reactant: CN
Solvent: CCO
Product: CNCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
4-{[2-(Trifluoromethyl)pyrimidin-5-yl]oxy}benzaldehyde was stirred with 33% methylamine in 95% ethanol (30 mL) at reflux for 1 hour and then concentrated. The residue was re-dissolved in 95% ethanol, 10% palladium/carbon was added, and the mixture was hydrogenated at room temperature under atmospheric pressure for 30 minutes. The reaction was performed on a 5.0 mmol scale with a yield of 95%.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 5.4 %

Procedure:
A mixture of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3, 2-(6-benzyl-pyridin-3-yl)-acetohydroximoyl chloride (88 mg, 0.34 mmol) described in Manufacturing Example 210-1-7, triethylamine (77 mg, 0.76 mmol), and tetrahydrofuran (5 mL) was stirred for 25 minutes at 50° C. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1, ethyl acetate) to obtain the title compound (4.6 mg, 5.3%).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][C:8]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]2[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[N:15]=[C:14]2[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=1)([O:3]C)=[O:2]>C(O)C.[OH-].[Na+]>[CH2:21]([C:14]1[N:13]([CH2:12][C:11]2[CH:25]=[CH:26][C:8]([O:7][C:6]3[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=3[C:1]([OH:3])=[O:2])=[CH:9][CH:10]=2)[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[N:15]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(Oc2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 87.5 %

Procedure:
A solution of 7.70 g of 1-[4-(2-carbomethoxyphenoxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 250 mL of ethanol and 125 mL of 10% aqueous sodium hydroxide was refluxed for 5 hours. After cooling, the reaction mixture was filtered, and the solvent was removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from acetone to furnish 6.52 g of 2-butyl-4-chloro-1-[4-(2-carboxyphenoxy)benzyl]-5-hydroxymethylimidazole, m.p. 178°-180°. NMR (200 MHz, DMSO) δ7.79 (d, 1H); 7.53 (t, 1H); 7.23 (t, 1H); 7.07 (d, 2H); 6.94 (d, 1H); 6.87 (d, 2H); 5.18 (s, 2H); 4.32 (s, 2H); 2.47 (t, 2H); 1.46 (quint., 2H); 1.23 (sext., 2H); 0.78 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25]C(=O)OCC)[C:9]=3[C:8]2=[O:31])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:31])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Oc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To the ethyl carbonate methoxymethyl ether 5 (70.9 mg, 0.156 mmol) in THF (7.6 mL) at room temperature was added a solution (5 mL) of K2CO3 (215 mg, 1.56 mmol) in water and 4-dimethylaminopyridine (3.8 mg, 0.03 mmol). The yellow solution was stirred at room temperature under nitrogen atmosphere overnight. Most of THF was removed under reduced pressure at 30-40° C. and the remaining solution was diluted with dichloromethane, washed with 1N HCl and brine, dried (MgSO4) and concentrated to give solid crude product (51 mg, 85%), which is triturated in diethylether/hexane to afford the product, 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo [3,4-g]quinoline-6,8-dione 6 as a yellow solid (34 mg). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7.4 (dd, 2H), 7.0 (t, 2H), 5.8 (s, 2H), 4.8 (s, 2H), 3.7 (s, 1H). MS: 383 (M+1); 381 (M-1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a 6° C. mixture of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (16 g, 48 mmol), AcOH (97 mL) and H2O (97 mL) was added NaNO2 (4.0 g, 58 mmol) in H2O (12 mL) dropwise over 15 min. After 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (6 mL) was added dropwise. After 1.5 hours, NaNO2 (0.5 g, 7 mmol) in H2O (2 mL) and a 1:1 mixture of concentrated sulfuric acid and water (5 mL) were added. The reaction was allowed to warm to room temperature overnight. The reaction was re-cooled in an ice bath and over a period of 1.5 hours, a 1:1 mixture of concentrated sulfuric acid and water (30 mL) and NaNO2 (1.5 g, 22 mmol) in H2O (5 mL) was added. Aqueous 3.75 M NaOH (210 mL) was added dropwise and the resulting suspension was filtered. The precipitate was washed sequentially with water and ether, then suspended in dichloromethane:ethanol (1:1) and filtered. The filtrate was washed sequentially with 1M aqueous Na2CO3 and brine, dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (9.6 g, 58%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C(N(CC)[C:16]([C:18]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH:33]([CH3:35])[CH3:34])=[CH:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)=[O:17])C.[Cl-].[NH4+]>O1CCCC1>[CH:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:16]2=[O:17])([CH3:35])[CH3:34]
Reactant: CCN(CC)C(=O)c1cc(OC)ccc1-c1ccccc1OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
Combine n-butyl lithium (22.00 mL of 2.5 M, 0.055 mole) and diisopropylamine (6.07 g, 0.060 mole), while stirring, in 150 mL tetrahydrofuran (THF) at -50° C. Wait approximately 5 minutes, then dropwise add N,N-diethyl-2'-isopropoxy-4-methoxy-biphenyl-2-carboxamide (3.80 g, 0.011 mole) dissolved in 50 mL THF. Remove the cooling source and allow the reaction to obtain ambient temperature, then stir while heating at 65° C. for 5 hours. The reaction changes color to orange, then to dark brown. Continue stirring the reaction overnight at ambient temperature overnight, then cool in an ice bath and neutralize with about 100 mL of a saturated solution of ammonium chloride. The reaction changes color to orange. Wash the THF solvent separately with brine (saturated sodium chloride) and dry over magnesium sulfate. Filter and concentrate to give a red liquid. Chromatography purification of this; material (20% ethyl acetate: 80% hexane) results in an orange liquid which solidifies when dried under high vacuum to give an orange solid (1.60 g, 50%). m.p. 89°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c2c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCNCC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-(1-benzyl-piperidin-4-ylamino)-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 100, 100 mg) and acetic acid (2 ml) in ethyl acetate (6 ml) was added 10% Pd on charcoal catalyst (20 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 3-methyl-4-[3-(piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (48 mg) as a colorless oil. FAB-MS: m/z 361 (MH+); 1H-NMR (CDCl3): δ 1.36 (2H, m), 1.43 (3H, t, J=7 Hz), 1.97 (2H, m), 2.07 (2H, quintet, J=6.5 Hz), 2.68 (3H, m), 2.74 (3H, s), 2.89 (2H, t, J=7 Hz), 3.17 (2H, br d, J=12.5 Hz), 4.16 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12)[CH3:20]
Reactant: CCO
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: [Na]
Product: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Reaction time: 1 h

Procedure:
Sodium (0.55 g, 23.7 mmol) was added portionwise to anhydrous ethanol (25 ml) at 20° C. under an atmosphere of nitrogen. After stirring for 1 hour the solution was added to Intermediate 1 (4.622 g, 18.22 mmol) and the reaction mixture heated at reflux for 2 hours. The mixture was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified on SPE cartridges (silica, 4×20 g) eluting with dichloromethane, ethyl acetate:petroleum ether (1:4, 1:2 then 1:1) followed by ethyl acetate). Appropriate fractions were combined and evaporated in vacuo to afford Intermediate 35 as white solid (4.33 g). LCMS showed MH+=264, TRET=2.77 min.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:38][CH:37]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)[CH2:36]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:38][CH:37]([N:39]5[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]5)[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C[C@@H]1CN(C2CNC2)C[C@H](C)O1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: C[C@@H]1CN(C2CN(C3=NC(=O)C(=Cc4ccc5c(cnn5Cc5ccc(C(F)(F)F)cc5C(F)(F)F)c4)S3)C2)C[C@H](C)O1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine following General Procedure C.