Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH3:46])[C:40](=[O:45])[N:41]([CH2:43][CH3:44])[CH:42]=1>>[CH2:43]([N:41]1[C:40](=[O:45])[C:39]([CH3:46])=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1)[CH3:44]
Reactant: CCn1cc(Br)cc(C)c1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCn1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)c1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethyl-3-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.314 min, m/z=489; 1H NMR (CDCl3) 1.09 (s, 3H), 1.15 (s, 3H), 1.35 (t, 3H), 1.50 (d, 3H), 2.15-2.25 (m, 7H), 2.35 (m, 1H), 2.86 (m, 1H), 4.03 (m, 2H), 5.66 (q, 1H), 6.96 (d, 2H), 7.13 (d, 2H), 7.25-7.36 (m, 7H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[O:20]=[C:19]1[NH:18][CH:17]=[CH:16][N:15]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:14]1[CH2:13][C:12]([NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:4][CH:5]=1)=[O:31]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CCl)cc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-chloromethyl-phenyl)-ethyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (195 mg, 0.42 mmol) in CH2Cl2 (2 mL) was added piperidine (Aldrich, 0.13 mL, 1.3 mmol) at rt. The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (50 mL). The organic solution was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative TLC (7% MeOH—CH2Cl2) afforded the title compound. MS (ESI): 511 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.CO>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: NO
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of methanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.6 parts of 1,4-diaminoanthraquinone-2-carboxylic acid.
Reaction SMILES: [OH:1][C@@H:2]([CH3:12])[C@H:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20]>O1CCCC1.O1CCOCC1>[CH2:22]([O:21][C:19]([NH:11][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[C@H:2]([CH3:12])[OH:1])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCOC(=O)Cl
Reactant: C[C@H](O)[C@H](N)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCCCCCOC(=O)N[C@H](c1cccc(O)c1)[C@H](C)O
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of (1R,2S)-2-hydroxy-1-(3-hydroxyphenyl)propylamine (17.2 g) in tetrahydrofuran (500 ml) was added 0.5M aqueous solution of sodium bicarbonate (500 ml) and the mixture was stirred at 0° C. To the mixture was added a solution of hexyl chloroformate (14 g) in dioxane (20 ml) and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→2:1→3:2) to give the title compound (24.2 g) having the following physical data.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of the alcohol (25 g, 80 mmol) produced in Example 2 and pyridine (6.4 mL, 80 mmol) in 300 mL of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (16.1 g, 80 mmol) in 200 mL of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, two times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 37.3 g of an off-white solid. Recrystallization from 1:1 ethyl acetate: hexane gave 26.4 g (69%) of the title compound as an off-white solid, mp 108-109° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>O>[C:14]12([C:7]3[C:8]([OH:10])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=3)[CH:4]=[O:5])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: O=Cc1ccc(O)cc1O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C

Procedure:
40 g (0.29 mol) of 2,4-dihydroxybenzaldehyde, 600 ml of dichloromethane and 46.4 g (0.34 mol) of 1-adamantanol were introduced into a round-bottomed flask and 24 ml of concentrated sulfuric acid were added. The reaction medium was stirred at room temperature for twelve hours and was then poured into water. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane. 50.8 g (64%) of the expected aldehyde, having a melting point of 259°-61° C., were recovered.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1([OH:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.[CH:30]1([NH:36][S:37]([OH:40])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH:30]1([NH:36][S:37](=[O:38])(=[O:39])[OH:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[C:19]([O:17][C:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CN(C)CCC1(O)CCCCC1c1ccccc1
Agent: O=S(=O)(O)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1(CCN(C)C)CCCCC1c1ccccc1

Procedure:
The procedure of Example I (c) is followed using 7.5 g of 1-(2-Dimethylaminoethyl)-2-phenylcyclohexanol (Example XIV) and 8 ml of acetyl chloride with 18 ml triethylamine giving 11.8 g crude acetate which is treated with 12 g cyclohexanesulfamic acid in tetrahydrofuran to give 6.7 g pure product, m. 140°-1°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:22][C:23]([CH3:25])=[O:24]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:22][C:23](=[O:24])[CH3:25])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
In a 250 ml single neck flask was charged 7.5 g (43.1 mmoles,1.0 eq) of m-trifluoromethylbenzaldehyde dissolved in 15 ml of acetone. To this was added 17.2 g of 10% aqueous sodium hydroxide solution (43 mmoles, 1.0 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 9.5 g of 4-(3-trifluoromethylphenyl)-3-buten-2-one as a faintly yellow oil in 88.7% yield.
Reaction SMILES: S(Cl)(Cl)=O.C[N:6](C)[CH:7]=[O:8].[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1C(O)=O>C1(C)C=CC=CC=1>[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:7]([NH2:6])=[O:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C

Procedure:
Thionyl chloride (3.95 g) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 8 in toluene (55 ml), and stirred at 80° C. for an hour. The solvent and an excess amount of thionyl chloride were evaporated, tetrahydrofuran (55 ml) was added to the residue, 25% aqueous ammonia (44 ml) was added under ice-cooling and stirred at room temperature for two hours. After the reaction, 1N aqueous solution of sodium hydroxide was added, and the precipitated solid was filtered to give 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (2.9 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[N:4][CH:5]=[C:6](Cl)[C:7]=1[O:8][CH2:9][CH3:10].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pd]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([F:12])[CH:2]=1)[CH3:10]
Reactant: [H][H]
Reactant: CCOc1c(Cl)cnc(F)c1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 60.5 g (0.31 mol) of 3,5-dichloro-4-ethoxy-2-fluoropyridine and 32.2 g (0.32 mol) of sodium acetate in 400 mL of ethanol in a L stirred steel Parr bomb was added 3 g of 5 percent palladium on carbon catalyst. The reactor was charged with 500 pounds per square inch gauge (3550 kiloPascals) of hydrogen and heated with stirring to 100° C. for 4 hr. The mixture was cooled, filtered, and concentrated by evaporation. The residue was dissolved in ether and the resulting solution was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by bulb to bulb distillation (60°-80° C. at 0.5 mm Hg (67 Pascals ) to obtain 18.5 g (42 percent of theory ) of the title compound as a colorless oil which solidified upon standing and melted at 35 °-36° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of 140 g. (0.8 mole) 2-acetyl-1,2,3,4-tetrahydroisoquinoline in 150 ml. dry methylene chloride at -15° C. with sufficient stirring was added dropwise 300 ml. (4.5 mole) chlorosulfonic acid. After the addition of the chlorosulfonic acid was complete, the reaction mixture was stirred for one hour at -15° C. and then heated to reflux for 2 hours. The reaction mixture was then cooled to 10° C. and then cautiously poured onto 3 l. of ice. The crude reaction product was then extracted in methylene chloride (2×150 ml.), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-7-chlorosulfonyl-1,2,3,4,-tetrahydroisoquinoline as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: N#Cc1ccc(-c2cc(NCc3ccccc3Cl)nc(N)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(NCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
To 4-(2-amino-6-{[(2-chlorophenyl)methyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (800 mg, 2.27 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by RPHPLC (BiotageSP1) (gradient: 30% CH3CN/H2O to 60% CH3CN/H2O) to afford the title compound (151 mg) as an off-white solid. LC-MS (ES) m/z=366 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 4.61 (d, J=5.6 Hz, 2H), 5.37 (s, 2H), 6.07 (s, 2H), 6.40 (s, 1H), 7.34-7.27 (m, 2H), 7.46-7.41 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CNCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: BrCC1CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 0.1 g of (4-bromo-phenyl)-[4-(6-methylamino-hexyloxy)-phenyl]-methanone, 0.13 ml of diisopropylethylamine and 0.06 ml of bromomethyl-cyclopropane in 20 ml of dimethyl-acetamide is stirred at 50° C. for 24 hrs., concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified over silica gel with CH2Cl2 /MeOH/NH4OH (94/5.410.6 to 85/12.5/2.5). There is obtained 0.68 g of (4-bromo-phenyl)-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-phenyl]-methanone which is converted into the fumarate, MS: m/e 443 (M+H+, 1Br).
Reaction SMILES: [CH2:1]([S:3][C:4]([S:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])=[S:5])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)(=O)C.C(O)(=O)C>[CH3:21][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9](=[O:10])[CH2:8][CH2:7][S:6][C:4]([S:3][CH2:1][CH3:2])=[S:5]
Reactant: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCSC(=S)SCCC(=O)N1CCC[C@H]1C(=O)OC

Procedure:
A solution of 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline in ethyl acetate is treated with an ethereal solution of diazomethane until persistent yellow color. After discharging the yellow color with a few drops of acetic acid, the solvents are removed in vacuo to yield 1-[3-[[(ethylthio)thiocarbonyl]thio]propanoyl]-L-proline methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1Cl)C2

Procedure:
A solution of 7-(2-chloro-5-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one in ethanol (10 ml) was combined with aminoguanidine hydrochloride (0.041 g), concentrated hydrochloric acid (0.078 ml) and water (0.078 ml), and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and the aqueous layer was washed with ethyl acetate. The aqueous layer was made alkaline with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1 ml) and concentrated. The resultant crystal was recrystallized from ethanol-ethyl acetate to obtain 7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound G) (0.05 g) as a colorless crystal.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[O:4]1.[F:10][C:11]1[CH:12]=[C:13]([NH:22][C:23]([C@@H:25]2[N:34]([C:35]([C@@H:37]3[CH2:40][C@H:39]([C:41]([OH:43])=[O:42])[CH2:38]3)=[O:36])[CH2:33][CH2:32][C:31]3[N:30]=[C:29]([O:44][CH3:45])[CH:28]=[CH:27][C:26]2=3)=[O:24])[CH:14]=[C:15]2[C:19]=1[C:18]([CH3:21])([CH3:20])[CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([NH:22][C:23]([C@@H:25]2[N:34]([C:35]([C@@H:37]3[CH2:40][C@H:39]([C:41]([O:43][CH2:2][C:3]4[O:4][C:5](=[O:9])[O:6][C:7]=4[CH3:8])=[O:42])[CH2:38]3)=[O:36])[CH2:33][CH2:32][C:31]3[N:30]=[C:29]([O:44][CH3:45])[CH:28]=[CH:27][C:26]2=3)=[O:24])[CH:14]=[C:15]2[C:19]=1[C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16]2
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: CC1OC(=O)OC1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)OCc3oc(=O)oc3C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxolan-2-one (0.026 mL, 0.24 mmol) was added to a mixture of cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutanecarboxylic acid (100 mg, 0.20 mmol) and potassium carbonate (33.5 mg, 0.24 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give the title compound (58.2 mg, 0.096 mmol, 47.5%) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[N:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)[CH2:5][CH2:4]1.[C:29]([O:33][C:34](=[O:49])[NH:35][CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([Cl:44])=[C:39]([N:45]=[C:46]=S)[C:38]=1[Cl:48])([CH3:32])([CH3:31])[CH3:30].CC(C)N=C=NC(C)C>>[F:28][C:2]([F:1])([F:27])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[CH:16]=[C:15]3[N:17]=[C:46]([NH:45][C:39]4[C:40]([Cl:44])=[C:41]([F:43])[CH:42]=[C:37]([CH2:36][NH:35][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:49])[C:38]=4[Cl:48])[NH:18][C:14]3=[N:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)=[O:26])[CH2:7][CH2:8]1
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)nc1N
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)nc3[nH]2)c1Cl

Procedure:
The subtitle compound is prepared in analogy to 2d from N-(trans-4-trifluoromethyl-cyclohexyl)-5,6-diamino-2-(4-fluoro-piperidinyl)-nicotinic acid amide, (2,4-dichloro-5-fluoro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester and DIC. The product is purified via prep. HPLC (C-18 stable bond, eluent gradient: water(+0.15% HCOOH)/MeOH 9:1->MeOH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: Brc1ccccn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cc2ccccc2n1-c1ccccn1
Yield: 30 %

Procedure:
A suspension of methyl 1H-indole-2-carboxylate (5.04 g), 2-bromopyridine (3.3 ml), potassium carbonate (7.9 g) and copper (II) oxide (3.9 g) in dry pyridine (80 ml) was heated under reflux for 48 hours. The solvent was removed in vacuo and dichloromethane added to the residue. After filtration the solvent was removed once again in vacuo and the resultant brown oil purified by column chromatography on silica eluting with diethyl ether in petroleum ether (bp 40°-60° C.). Methyl 1-(2-pyridyl)-1H-indole-2-carboxylate was obtained as a white solid: yield 4.74 g (65%). NMR (CDCl3) 3.7 (3H,s,CH3), 7.46 (8H,m,Ar--H), 8.60 (1H,m,Ar--H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccnc(CO)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccnc(CCl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-tert-butyl-2-hydroxymethylpyridine (0.36 g) in chloroform (10 ml) was added dropwise a solution of thionyl chloride (1 ml) in chloroform (5 ml) at room temperature and the mixture was stirred for 3 hours at ca. 50° C., After cooling to room temperature, the resultant mixture was concentrated in vacuo. The residue was taken up with chloroform and washed with saturated sodium carbonate aqueous solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-tert-butyl-2-chloromethylpyridine (0.37 g) as a brown oil.