Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[H-].[Na+].[F:9][C:10]([F:29])([F:28])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20]([CH3:26])([CH3:25])[C@@H:19]1[O:27][C@H:18]21.O>CS(C)=O>[OH:27][C@@H:19]1[C@@H:18]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][C:10]([F:29])([F:9])[F:28])[CH:16]=2)[O:21][C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)Oc2ccc(OCCCC(F)(F)F)cc2[C@H]2O[C@H]21
Reactant: CNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNS(=O)(=O)C[C@H]1c2cc(OCCCC(F)(F)F)ccc2OC(C)(C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Under argon, 0.77 g (7.1 mmol) of N-methyl-methanesulfonamide was added to a suspension of 0.065 g (2.7 mmol) of 80 percent sodium hydride in 3 ml of DMSO, and the mixture was stirred at RT for 20 min. 1.65 g (5.5 mmol) of (3R,4R)-(+)-6-(4,4,4-trifluorobutoxy)-2,2-dimethyl-3,4-epoxychroman, dissolved in 5 ml of DMSO, were then added dropwise and the batch was left to stand at RT for 4 days and then heated at 45° C. for a further 9 h. The mixture was subsequently poured into water and the precipitate was filtered off with suction and dried thoroughly under reduced pressure, giving 1.9 g of (3R,4S)-(+)-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-methanesulfonamide, which was recrystallized from a little isopropanol (->1.4 g; m.p. 178-179° C.; optical purity (chiral HPLC) 100%).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(C(=O)OCC)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.48 g of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate and 1.5 ml of triethylamine in 10 ml of dry tetrahydrofuran was added dropwise 1 ml of ethyl chloroformate at 5° C. or below, and the mixture was stirred at room temperature for 2 hours. The resulting solid was removed by filtration, and the filtrate was evaporated to dryness to give crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphthoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[C:5](=[CH:6][C:7]([N:11]([C:20]([O:22]C(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:9]=2)[C:4]([CH3:28])([CH3:27])[CH2:3]1.FC(F)(F)C(O)=O.[C:37](OCC)(=O)[CH2:38][C:39](C)=O>C(O)(=O)C>[CH3:37][C:38]1[CH2:39][C:20](=[O:22])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[C:2]([CH3:29])([CH3:1])[CH2:3][C:4]3([CH3:28])[CH3:27])[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3(C)C)C(=O)C1
Temperature: 100 °C
Yield: 12.5 %

Procedure:
Di-tert-butyl 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 19c (2.70 g, 7.18 mmol) was dissolved in 10 mL of acetic acid followed by addition of 13 mL of trifluoroacetic acid. After the mixture was reacted at room temperature for 30 minutes, ethyl acetoacetate (502 mg, 3.86 mmol) was added. The reaction mixture was heated to 100° C. and reacted for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The mixture was neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(1,1,3,3-tetramethyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 19d (130 mg, yield 13.6%) as a light yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:20][N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][C:19]([CH2:22][C:23]([NH:33][CH2:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:25])=[CH:20][N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2ncc(CC(=O)O)s2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2ncc(CC(=O)NCC3CCOCC3)s2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 2 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][N:17]2[CH:26]=1)[C@@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][N:17]2[CH:26]=1)[C@@H:9]([CH3:13])[C:10]([NH2:12])=[O:11]
Reactant: C[C@@H](C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(C(C)(C)C)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(N)=O)[C@H](N)c1cn2cc(C(C)(C)C)ccc2n1
Reaction time: 18 h
Yield: 102.3 %

Procedure:
tert-Butyl((1S,2R)-3-amino-1-(6-(tert-butyl)imidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxopropyl)carbamate (Preparation 37, 311 mg) was dissolved in dichloromethane (ca 4 mL) and excess trifluoroacetic acid (ca 0.5 mL) was added. The reaction mixture was stirred for 18 hours then the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The product stayed in the aqueous phase. The aqueous phase was adjusted to pH=10 with 1N sodium hydroxide, then sodium chloride was added until the solution was saturated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% CMA80 in dichloromethane to afford 233 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:17]I.[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:17])=[N:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccc(Cl)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Yield: 91.2 %

Procedure:
A Solution of 5-(4-chlorobenzyl)-2-thiouracil (50.5 g), methyl iodine (28.4 g) and sodium hydroxide (8.2 g) in water (200 ml) and ethanol (400 ml) was stirred at 60° for 30 minutes then allowed to cool. The crystalline product was filtered and washed with water to give 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (48.6 g), m.p. 193°-194° (methanol/ethanol).
Reaction SMILES: [CH2:1]([OH:11])[C@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C(Cl)Cl>[C:12]1([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][CH2:9][C@H:7]2[O:8][C@H:2]([CH2:1][O:11][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:3]([OH:4])[C@@H:5]2[OH:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
a mixture of 2.35 g (14.33 mmol) of 2,5-anhydro-D-mannitol and 8.79 g (31.53 mmol) of triphenylmethyl chloride in 38 ml of pyridine was stirred at 100° C. for 12 hours. After cooling, the mixture was diluted with CH2Cl2, and washed with aq.HCl (0.78 mol/l), the organic phase was dried over Na2SO4 and the solvent was subsequently removed under reduced pressure. The crude product was purified by means of column chromatography (hexane/ethyl acetate 2:1). Yield: 5.57 g (60% of theory).
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[Mg].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH2:4][CH3:5]
Reactant: CCC(C)Br
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
Add slowly a solution of 2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirring mixture of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. Heat the mixture at reflux for 30 min. Cool the mixture to room temperature and add 4-bromo-benzaldehyde (5.36 g, 29 mmol). After stirring for 5 min, cool the mixture in an ice-bath and acidify with 3N aqueous HCl (50 mL). Dilute the mixture with water and extract twice with diethyl ether. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 20:1 and 1:1) to provide the desired intermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)+.
Reaction SMILES: [K].Br[CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH:13][C@H:3]([C:4]([OH:6])=[O:5])[CH:7]([CH3:9])[CH3:8]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)C(Br)C(=O)O
Agent: [K]
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
N-(2-fluoro-4-chlorophenyl)valine and m-phenoxybenzyl bromide are reacted using the process of Example 42 to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 427.1 (M+, 4.1), 200 (100). N-(2-fluoro-4-chlorophenyl)-valine is prepared by heating the potassium salt of α-bromoisovaleric acid and 2-fluoro-4-chloroaniline neat at 130° for about 2 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cccc(Nc2ccc(C(F)(F)F)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-aminobenzotrifluoride according to general procedure A provided methyl ester of Compound 7 as a white solid (86% yield). 1H NMR (CDCl3, 500 MHz): δ=7.82 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.33 (m, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.11 (bs, 1H), 3.93 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.0, 146.3, 141.9, 131.8, 129.8, 127.0, 123.9, 120.5, 116.1, 52.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:27][CH:28]([CH3:30])[CH3:29].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:10])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN(c1cccc(Cl)c1)S(=O)(=O)Cc1ccc(Br)cc1
Temperature: 100 °C
Yield: 59.5 %

Procedure:
To a mixture of C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol) and K2CO3 (464 mg, 3.4 mmol) in dimethylformamide (5 mL) was added 1-iodo-2-methylpropane (584 μL, 5.0 mmol). The mixture was heated at 100° C. in microwave reactor for 3 hours. Water was added and the reaction extracted with EtOAc, washed with brine, dried with Na2SO4, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-N-isobutyl-methanesulfonamide (423 mg, 1.0 mmol, 60%). LCMS (m/z, Method A) ES+ 415.8 [M+1]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: N#CNC(=Nc1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), aniline (0.32 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.63 g, 2.8 mmol, yield: 91%) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]1([N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N(c1ccccc1)c1ccccc1

Procedure:
3,4-Dichloroaniline (5.35 g, 0.033 mol) was dissolved in 100 ml of chloroform and 7.65 g (0.033 mol) of diphenylcarbamic chloride and 3.33 g (0.033 mol) of triethylamine were added.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=3[F:36])[CH:18]=2)[NH:13][CH:12]=1)=[O:10]>CCO>[F:36][C:23]1[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[C:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9](=[O:10])[CH2:8][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1)=[O:37]
Reactant: C1CCNCC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN4CCCCC4)c3c2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Piperidine (0.0105 mL, 0.106 mmol) was added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.0106 mmol) in EtOH (0.2 mL), which was stirred at 60° C. for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified via column chromatography (10% MeOH/EtOAc, to 30% MeOH (7N NH3/EtOAc). The pooled fractions were taken up in 10% MeOH/DCM and filtered to provide 2,6-difluoro-N-(3-(2-(piperidin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (3 mg, 54.4%). 1H NMR (400 MHz, CD3OD) δ 9.05-9.07 (m, 1H), 8.54-8.57 (m, 1H), 8.44 (s, 1H), 7.63-7.69 (m, 1H), 7.12-7.17 (m, 1H), 4.71 (s, 2H), 3.59 (s, 2H), 3.10-3.14 (m, 2H), 1.92-1.99 (m, 6H), 1.84-1.90 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=520.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 4 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetyl-thiourea, 2.1 ml (0.015 M) of ground potassium carbonate, 3.2 ml (0.03 M) of n-butylbromide and 50 ml of acetone are boiled in a reflux under energetic shaking for 4 hours. The acetone is distilled off. The residue in the flask is washed with water and filtered. 5.8 g (90.6% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-n-butylisothiourea with a melting point of 84°-89° are obtained. After recrystallization from ethanol the product has a melting point of 97°-100°.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]2[CH:3]1[CH2:1][CH3:2])=[O:22]
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
5-(2,4-Dimethoxybenzoyl)-4-ethyl-7-fluoro-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and 2,4-dimethoxy benzoyl chloride according to the procedure of Example 106, Step 2, mp 131-132° C. MS (ESI) m/z 381; Anal. Calcd for C22H21FN2O3: C, 69.46; H, 5.56; N, 7.36. Found: C, 69.22; H, 5.63; N, 7.32.
Reaction SMILES: [H-].[Na+].O.[F:4][C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) is suspended in dry DMF (10 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice:water. To above suspension is added dropwise over 15 minutes (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 4 hours. The reaction mixture is poured into 300 ml of ice:water. The resultant solid is isolated by suction filtration, washed with water (500 ml), and air dried to yield 5.5 g (20 mmol, 83%) of the clean desired material as an yellow powder.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[CH:11]=2)[CH:2]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 41 mg of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[4-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in 5 ml dichloromethane and purified by flash chromatography (dichloromethane/methanol, 95/5 (v/v)) to yield the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]4[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[CH:2]1.ClC(Cl)(Cl)C[O:26][C:27](=O)[NH:28][C:29]1[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:27]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:7][C:8]4=[N:14][CH:13]=3)=[CH:16][CH:17]=2)=[O:26])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: NCc1ccc(-c2cnc3cc(-c4ccsc4)ccn23)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2ccc(-c3cnc4cc(-c5ccsc5)ccn34)cc2)cc1
Temperature: 62 °C
Yield: 21.6 %

Procedure:
Dissolve 4-(7-thien-3-yl-imidazo[1,2-a]pyridin-3-yl)-benzylamine (0.058 g, 0.19 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.093 g, 0.23 mmol) and diisopropylethylamine (0.071 g, 0.55 mmol) in DMSO (3.6 mL). Heat the mixture at 62° C. for 8 hours. After evaporation of solvent, dilute the reaction with water and ethyl acetate. Extract the water phase with ethyl acetate and wash the combined organic layers with saturated aqueous saturated sodium chloride and evaporate to dryness. Purify the residue by silica gel column chromatography (dichlromethane/ethyl acetate gradient) to give 0.023 g (21% yield) of desired compound: MS(ES), m/z 561 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][S:15]([CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)(=[O:17])=[O:16]>>[CH3:14][S:15]([CH:18]1[CH2:22][CH2:21][N:20]([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)C1CCNC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)C1
Yield: 44.1 %

Procedure:
The title intermediate is prepared from 4-(chlorosulfonyl)benzoic acid (CAS 10130-89-9) (375 mg, 1.7 mmol) and 3-(methylsulfonyl)pyrrolidine (CAS 433980-62-2) (343 mg, 2.3 mmol) in a manner substantially similar to Procedure F to provide 250 mg (44%) of the title compound. MS (ES−) 332.0 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N=C=S
Reactant: NC(CO)c1cccc(Br)c1
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)c1cccc(Br)c1

Procedure:
A solution of 3.54 g of 2-amino-2-(3-bromophenyl)-1-ethanol, in 20 cm3 of ethanol containing 0.18 cm3 of tert-butyl isothiocyanate is stirred at a temperature in the region of 20° C. for 5 hours. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 25 cm3 of petroleum ether. The resulting crystals are spin-filtered, washed with twice 25 cm3 of petroleum ether and then dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. 4 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-bromophenyl)ethyl]thiourea are obtained in the form of a white solid (Rf=0.68 in a 40/5/0.5 by volume dichloromethane/methanol/aqueous ammonia mixture, on a Merck 60F254R silica plate)