Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:38]1([NH:37][C:5]2[N:6]=[C:7]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=3)[C:8]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10][C:9]=3[N:25]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2nc(Nc3ccccc3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Yield: 61.2 %

Procedure:
A solution of [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 30 mg, 0.06 mmol), aniline (8 mg, 0.09 mmol), and p-toluenesulfonic acid (21.3 mg, 0.11 mmol) in toluene (2 mL) was heated at 125° C. for 12 h. The mixture was cooled and directly purified using Preparative HPLC to give the title compound (20 mg, 67%). MS (ESI): mass calcd. for C27H22F6N6, 544.18; m/z found, 545.9 [M+H]+. 1H NMR (CD3OD): 8.46-8.44 (m, 1H), 8.00-7.97 (m, 1H), 7.66-7.58 (m, 4H), 7.48 (s, 1H), 7.45-7.42 (m, 2H), 7.24-7.19 (m, 2H), 7.16-7.11 (m, 2H), 3.63-3.59 (m, 2H), 3.57-3.53 (m, 2H), 3.29-3.25 (m, 2H), 3.11-3.07 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[F:11][CH:12]([F:21])[O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CS(C)=O>[F:11][CH:12]([F:21])[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 666 μL (5.52 mmol) of 4-fluoroacetophenone and 883 mg (5.52 mmol) of 4-(difluoromethoxy)phenol in 10 mL DMSO was combined with 1.91 g (13.78 mmol) of potassium carbonate and stirred overnight at 100° C. The reaction mixture was poured onto 250 mL semisaturated sodium chloride solution and extracted twice with tert-butylmethylether. The organic phase was dried and evaporated down. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(#N)C>[Si:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N[C@@H](CCO)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol, 1.05 eq). tert-butyldimethylsilyl chloride (1.33 g, 8.8 mmol, 1.05 eq) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate formed, which was filtered off and washed with acetonitrile before drying under reduced pressure. The title compound was isolated as a white solid (1.8 g, 92% yield). 1H NMR (500 MHz, DMSO-d6), δ: 7.5 (1H, br s), 3.7 (1H, m), 3.35 (4H, br m), 1.95 (1H, m), 1.70 (1H, m), 0.9 (9H, s), 0.1 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].C(N(C(C)C)C(C)C)C.[C:21]([NH:38][CH2:39][C:40](Cl)=[O:41])([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>C1COCC1.C(Cl)Cl.C1COCC1>[CH:27]1[C:26]2[CH:25]([CH2:24][O:23][C:21]([NH:38][CH2:39][C:40]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[Cl:11])=[O:41])=[O:22])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 4-amino-3-chlorobenzoic acid (1.5 g; 8.75 mmol) and N-ethyldiisopropylamine (1.46 mL 8.75 mmol) in THF (50 mL) was added dropwise to a solution of Fmoc-glycylchloride (2.76 g; 8.75 mmol) in CH2Cl2/THF 1:1 (30 mL) and stirred at room temperature under N2. After 3 h the solvent was evaporated under vacuum. The residue was taken up with 0.5N HCl (50 mL), filtered and dried. The white solid was suspended in MeOH (30 mL) and stirred for 1 h, then was filtered and dried to give 4-[[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino-3-chlorobenzoic acid (2.95 g; 6.5 mmol). Yield 75%.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:21])[CH:12]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH3:22])/[CH:3]=[CH:4]/[C:5](=[S:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:21])[CH:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(NCCNC(=O)/C=C/C(C)C)c2ccccc2n1
Solvent: C1COCCO1
Product: Cc1cc(NCCNC(=S)/C=C/C(C)C)c2ccccc2n1
Temperature: 130 °C

Procedure:
(E)-4-Methyl-N-[2-[(2-methyl-4-quinolyl)amino]ethyl]pent-2-enamide (50 mg, 0.15 mmol) was dissolved in dioxane (2 ml), Lawesson's reagent (75 mg, 0.18 mmol) was added in one portion and the resulting mixture was stirred at 130° C. under microwave heating for 0.5 hrs. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 15 mg (0.047 mmol, 28.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@H:18]1[CH2:22][NH:21][CH2:20][C@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cnc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (40 mL) were added phenylmethyl {[(3S,4R)-4-hydroxypyrrolidin-3-yl]methyl}carbamate (0.658 g, 2.29 mmol) and triethylamine (0.351 mL, 2.52 mmol). The resulting solution was stirred at ambient temperature for 1 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred at rt for an additional 18 h. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil (0.760 g, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH:8]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5.3 g) obtained in Step B of Example 131 in ethanol (30 mL) was added 5% palladium-carbon (4.2 g), and the mixture was stirred at room temperature for 2 hr under hydrogen atmosphere (at normal pressures). The palladium-carbon was removed by filtration through Celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[I:12]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: ClCc1cn2ccccc2n1
Solvent: CC#N
Product: ClCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
5 g (30 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were solubilised in 60 ml of acetonitrile with magnetic stirring, 7.31 g (31.5 mmol) of N-iodosuccinimide were added and the mixture was stirred at r.t. for 15 min. The solid formed was isolated by filtration, washed with 30 ml of water and dried in a vacuum bell jar. 8.46 g (yield=95%) of 2-(chloromethyl)-3-iodoimidazo[1,2-a]pyridine were obtained as a white solid. LC-MS: m/z=293 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.31 (d, J=6.9 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.46-7.29 (m, 1H), 7.07 (td, J=6.8, 1.0 Hz, 1H), 4.81 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH:9]([O:11][CH3:12])[CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]2[CH2:20][CH2:21][CH:22]=[CH:23][CH:15]12.C(O)(=O)C>C(OCC)C>[Cl:1][C:2]1[C:8]([CH:9]([O:11][CH3:12])[CH3:10])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: COC(C)c1cc(N)c(F)cc1Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(C)c1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 40.8 %

Procedure:
A mixture of 0.58 g (0.0029 mole) of 4-chloro-2-fluoro-5-(1-methoxyethyl)aniline, 0.82 g (0.0054 mole) of tetrahydrophthalic anhydride, and 15 ml of acetic acid was refluxed overnight. The acetic acid was then evaporated under reduced pressure, leaving a residue which was dissolved in diethyl ether. This solution was washed successively with water and an aqueous solution of sodium bicarbonate. The solution was dried, filtered, and the solvent was evaporated under reduced pressure leaving a residue. This residue was passed through a silica gel column, eluting with ethyl acetate/heptane (1/4). Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 0.4 g of N-[4-chloro-2-fluoro-5-(1-methoxyethyl)phenyl]-3,4,5,6-tetrahydrophthalimide as a solid, m.p. 141°-44° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].Cl[C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>O1CCCC1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: [O-]CCCN1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2sc(OCCCN3CCCCC3)nc2c1

Procedure:
Sodium 3-piperidinopropanolate (5 mmol) and 5 mmol of 2-chlorobenzothiazole in 20 ml of dry tetrahydrofurane were refluxed for 12 hours. The suspension was filtered and the solvent evaporated under reduced pressure. The product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].Cl>C(O)C.[Fe]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(N)cc2)cc1OC
Temperature: 25 °C
Yield: 108.4 %

Procedure:
Iron powder (0.58 g, 10 mmol) was added to a solution of methyl 3-methoxy-4′-nitrobiphenyl-4-carboxylate (0.38 g, 1.0 mmol) in ethanol (10 mL). Concentrated HCl (0.52 mL, 1.0 mmol) was added, and the mixture was heated at reflux for 3 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.279 g (quantitative yield) of the title compound. LC/MS m/z 258.3 (MH+); retention time 1.65 min. 1H NMR (400 MHz, CD2Cl2) 3.81 (s, 3H), 3.99 (s, 3H), 6.78 (d, 2H), 7.15-7.19 (m, 2H), 7.45 (d, 2H), 7.80 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1>[Pt](=O)=O.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:3]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: CC(C)(O)Cn1c(N)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1c(N)nc2c(N)nc3c(c21)CCCC3
Reaction time: 192 h
Yield: 56.5 %

Procedure:
1-(2,4-Diamino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (0.50 g, 1.8 mmol), trifluoroacetic acid (200 mL), and platinum (IV) oxide (300 mg) were added to a Parr vessel and shaken under hydrogen pressure (45 psi, 3.1×105 Pa) for eight days. The volatiles were removed under reduced pressure, and the residue was dissolved in methanol and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure, and the resulting solid was dissolved in methanol. Hydrogen chloride (30 mL of a 4 M solution in dioxane) was added, and the resulting solution was stirred for two hours. Ammonia (7 M in methanol) was added, and the volatiles were then removed under reduced pressure. Ammonia (7 M in methanol was added a second time, and the resulting mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica cartridge, eluting with 0-8% methanol in dichloromethane with aqueous ammonium hydroxide added). The resulting white solid was washed with hot acetonitrile and dried in a vacuum oven to provide 280 mg of 1-(2,4-diamino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white solid, mp >270° C.
Reaction SMILES: O.O.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C(O)C.[F:16][C:17]([F:25])([F:24])[C:18]([CH2:20][C:21](=O)[CH3:22])=O>CCOCC>[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[N:10]=[C:21]([CH3:22])[CH:20]=[C:18]([C:17]([F:25])([F:24])[F:16])[N:9]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)c1ccc(O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nc(-c2ccc(O)cc2)n1

Procedure:
In a pressure tube a mixture of 17.2 g of 4-hydroxybenzamidine dihydrate, 60 ml of ethanol and 14.6 ml of trifluoroacetylacetone is heated for 18 hours at a bath temperature of 110°. The mixture is then stirred with 200 ml of ether, a small amount of precipitate is filtered off with suction and the filtrate is extracted with two portions of 2N sodium hydroxide solution. The alkaline solution is treated with carbon, filtered and then 400 ml of ethyl acetate and 160 ml of 2N hydrochloric acid are added to pH 1. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from ether/hexane yielding 2-(4-hydroxyphenyl)-4-methyl-6-(trifluoromethyl)-pyrimidine having a melting point of 131°-132° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2cccc(C)n2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(COc2cc(C(C)(C)C)nn2Cc2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution (20 mL) of methyl 4-({3-tert-butyl-5-[(6-methylpyridin-2-yl)methoxy]-1H-pyrazol-1-yl}methyl)benzoate (2.14 g, 5.44 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.26 g, 5.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (1.0 mL) were added to the reaction mixture. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=3:1) to give the title compound (1.86 g, yield 94%) as a yellow oil. 1H NMR (CDCl3) δ: 1.26 (9H, s), 2.24 (1H, br s), 2.53 (3H, s), 4.64 (2H, br s), 5.09 (2H, s), 5.17 (2H, s), 5.43 (1H, s), 6.97-7.08 (2H, m), 7.10-7.16 (2H, m), 7.23-7.30 (2H, m), 7.51 (1H, t, J=7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[C:5]([CH3:19])[C:4]=2[F:20])[CH2:31]1
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 0.50 g (1.60 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.36 g (1.93 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.48 g (4.75 mmol) of triethylamine, and 20 mL of acetonitrile was refluxed for 4 hours, then stirred at room temperature overnight. The solution was concentrated and the residue was triturated with ether:hexane (1:1) and filtered. The solid was washed with water and hexane. The crude product was suspended in 15 mL of dichloromethane and 1.5 mL of trifluoroacetic acid and was stirred at room temperature for 4 hours. The solution was concentrated to a gold solid which was suspended in water, made basic (pH 11) with 10% sodium hydroxide, and filtered. The solution was then neutralized (pH 7.1), and the precipitate was collected by filtration, washed with water, and dried in vacuo to give 0.29 g of the title compound, mp 124°-126° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[NH:32][C:31]([CH3:30])=[N:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: Cc1nnc(CC(=O)N2CCN(c3ccc4c(C(C)C)nn(C5CCC5)c4c3)C[C@@H]2Cc2ccccc2)[nH]1
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 189 from 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-isopropyl-1H-indazole and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (35 mg, 25%). LC/MS (Method B) 3.62 min, [M+1]+ 512.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](=[O:14])(=[O:13])[NH:19][CH:16]1[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Reaction time: 3 h
Yield: 35 %

Procedure:
A round bottom flask was charged with methyl 4-chloro-3-(chlorosulfonyl)benzoate (12.0 g, 44.32 mmol) and 1,4-dioxane (100 mL) at 0° C. Cyclopropyl amine (9.31 mL, 137.8 mmol) was added dropwise and the mixture was stirred at that temperature for 3 h. The solvent was removed and the residue was treated with EtOAc. The organic phase was washed with brine, dried, and concentrated to get the title compound (4.5 g, 32% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]

Procedure:
5-Bromo-2-methyl-2-pentene (15 g, 0.092 mol) was added to a slurry of 2-nitroimidazole (10.4 g, 0.092 mol) and potassium carbonate (12.7 g, 0.092 mol) and refluxed for 24 hrs. Acetone was removed on a rotary evaporator and the residue was purified by column chromatography. Yield 6.2 g (34%). 1H NMR CDCl3) δ1.44 and 1.68 [s, 6H, =C(CH3)2 ], 2.53 (m, t 2H, CH2CH2CN<), 4.41 (t, 2H, CH2CH2CN<), 5.06 (m, 1H, CH=C), 7.03 and 7.12 (s, 2H, imi H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([NH2:10])[CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:17][C:18](Br)=[O:19].CCOC(C)=O>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[O:9][CH2:17][C:18](=[O:19])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(O)cc1C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C)OCC(=O)N2
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 4,5-dimethyl-2-aminophenol (1.73 g, 12.6 mmol) in chloroform (50 mL) was added to a rapidly stirred saturated solution of sodium bicarbonate. Bromoacetyl bromide (1.1 mL, 2.54 g, 12.6 mmol) in chloroform (15 mL) was added dropwise to the rapidly stirring mixture. Stirring continued for 2 h. EtOAc was added. Layers separated and the EtOAc solution washed with H2O (1×), brine (1×), dried (MgSO4) and concentrated to give a brown solid, which was dissolved in DMF (85 mL). CsCO3 (4.1 g, 12.6 mmol) was added and the mixture heated at 80 deg. C. for 1 h, then poured into ice-H2O (200 mL). The crystallized product was collected, washed with H2O, and dried to give a tan solid (1.78 g, 80%). MS (ES) m/e 178[M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[S:8][CH:9]=1)=[O:4]>[OH-].[Na+]>[CH3:14][S:11]([NH:10][C:7]1[S:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1csc(NS(C)(=O)=O)n1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 2-methanesulfonylamino-thiazole-4-carboxylic acid methyl ester (5.5 g, 22 mmol) in 1M NaOH(50 mL) was stirred at rt for 1 h. The reaction mixture was extracted with ethyl acetate, concentrated and chromatographed on silica gel (ethyl acetate/ethanol, 97:3) to provide 2-methanesulfonylamino-thiazole-4-carboxylic acid (3.7 g) as a solid. MS (ESI−) for C5H6N2O4S2 m/z 220.9 (M−H)−.