Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=2[C:15]#[N:16])[CH2:7][CH2:6]1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:14]=2[C:15]([NH2:16])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:9][CH2:10]1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2Cl)CC1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCC(Cc4ccccc4Cl)CC3)cccc2n1
Yield: 79 %

Procedure:
Cyclization of 2-[4-(2-chlorobenzyl)cyclohexylmethoxy]-6-fluorobenzonitrile (100 mg; 0.28 mmol) was carried out using Method F using guanidine carbonate (100 mg; 0.55 mmol) in 1.5 mL of dimethylacetamide. Title compound was obtained as a white solid. (88 mg; 79% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.27 (m, 7H), 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.97 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 1.83 (m, 3H), 1.68 (m, 3H), 1.06 (m, 4H). MS m/z (ESI) 398 (M+H)+.
Reaction SMILES: C([S:9][CH:10]([CH3:22])[C:11]([NH:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:12])(=O)C1C=CC=CC=1.[OH-].[Na+]>>[SH:9][CH:10]([CH3:22])[C:11]([NH:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:12]
Reactant: CC(CCCC(=O)O)NC(=O)C(C)SC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(CCCC(=O)O)NC(=O)C(C)S
Yield: 61.8 %

Procedure:
12.4g of N-(2-benzoylmercaptopropionyl)-5-aminocaproic acid was hydrolized with NaOH in a similar manner as described in Example VIII to give 5.2g of N-(2-mercaptopropionyl)-5-aminocaproic acid, ##EQU12##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.[Na].C([O:24][C:25](=O)[C:26]([CH3:29])=[CH:27]O)C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:25]([OH:24])=[C:26]([CH3:29])[CH:27]=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)=CO
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Temperature: 100 °C
Yield: 29.5 %

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 393 mg, 1.29 mmol) in acetic acid (4.3 ml) was added 3-hydroxy-2-methylacrylic acid ethyl ester sodium salt (590 mg, 3.88 mmol), portionwise. The reaction was heated at 100° C. for 2 hours (precipitate formed after 35 minutes). After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-3A-1c as a colorless solid (141 mg, 30%): +ESI MS (M+1) 370.0; 1H NMR (400 MHz, DMSO-d6) δ 12.14 (br s, 1H), 7.75 (s, 1H), 7.50–7.38 (m, 4H), 7.32 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 2.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].Cl[CH2:32][P:33](=[O:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:32][P:33]([CH3:35])([CH3:34])=[O:36])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CP(C)(=O)CCl
Reactant: CC(Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cnn(C3CCN(CP(C)(C)=O)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 42.7 %

Procedure:
A mixture of 3-(1-(2,6-dichloro-3-fluoro-phenyl)ethoxy)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-amine (6 mg, 0.013 mmol), chloromethyl-dimethyl-phosphine oxide (100 mg, 0.79 mmol), and potassium carbonate (0.2 g) in DMF (5 mL) was heated to 80° C. overnight. The solid was removed and the residue was purified by HPLC (water/methanol, 10˜100%) to give the title compound as an off-white solid (3 mg, 40%); ESMS: m/z 540 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)=[O:28].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 85.4 %

Procedure:
The thus-obtained tert-butyl 4-({[3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl]carbonyl}amino)piperidine-1-carboxylate (610 mg) and trifluoroacetic acid (5 mL) were stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=20/1), and the obtained solid was recrystallized from ethyl acetate-ethanol to give the title compound (430 mg, 85%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[C@H:13]([CH2:20]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:17])([F:18])[F:19])[C@H:13]([CH2:20][N:26]2[C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]3[C:22]2=[O:32])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@H](C(F)(F)F)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@@H](CN2C(=O)c3ccccc3C2=O)[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
In 250 ml of absolute tetrahydrofuran, is dissolved 8.0 g (26.4 mmol) of trans-1-benzyloxycarbonyl-3-hydroxymethyl-4-trifluoromethylpyrrolidine. To the above solution, are added 4.27 g (29.0 mmol) of phthalimide and 8.30 g (31.7 mmol) of triphenylphosphine. Further, 5.0 ml (31.7 mmol) of azo dicarboxylic acid diethyl ester is added dropwise to the above solution on cooling with ice. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the concentrated mixture to give a precipitate. The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (elusion solvent; chloroform/n-hexane (4/1→8/1)) to give 9.72 g of the objective substance as a colorless powder (yield 85.2%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[Cl:61]C1C=C(N=C=S)C=CC=1>>[Cl:61][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(Cl)c4)cc3)ccc2C1=O

Procedure:
The compound of example 266 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-chlorophenyl isothiocyanate. The compound of example 266 was used directly without isolation for the preparation of compound of example 267.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C1COCC1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:4]2[N:3]=[C:2]3[NH:1][C:35](=[O:36])[N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)=[N:17]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)NCC(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2c(=O)n1CC(F)(F)F
Reaction time: 0.42 h

Procedure:
50 mg (0.11 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide (example 103A) were initially charged in 5 ml of THF and, while cooling with ice, 18.0 mg (0.45 mmol) of sodium hydride (60% in mineral oil) were added over a period of 5 min. The mixture was stirred for 25 min, then 27.3 mg (0.17 mmol) of 1,1′-carbonyldiimidazole were added with ice cooling over 5 min. Conversion was effected at room temperature for 1 h and at reflux temperature for 90 min. After cooling, the mixture was hydrolyzed and then the organic phase was diluted with 10 ml of THF. After drying with sodium sulfate, the volatile components were removed by means of a rotary evaporator. Then the crude material was purified by means of preparative HPLC [column: Reprosil C18, 10 μm, 250*30 mm; flow rate: 40 ml/min; eluent: methanol/0.05% formic acid; gradient: 50% methanol→95% methanol)]. The volatile components of the product fractions were removed on the rotary evaporator. Thus, 26 mg (48% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:5]=3[C:4]=2[CH:3]=1.OS(O)(=O)=O.[OH-].[K+]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(n(CC(C)(O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The title compound was prepared by following general procedure 6. 1-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol (100 mg, 0.259 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 3 h. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 12 mg of product as the TFA salt along with 9-chloro-6-(2-(4-fluorophenyl)allyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole. Compound No. 82: 1H NMR (CDCl3, freebase) δ (ppm): 7.50-7.30 (m, 3H), 7.20-7.00 (m, 4H), 7.30-7.20 (d, 1H), 5.00-4.90 (t, 2H), 4.40-4.30 (d, 1H), 3.10-2.90 (m, 8H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[O:8][CH2:7]1.CI.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:14]1[C:9]2[O:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][C:13]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -78 °C
Reaction time: 7 h

Procedure:
A solution of n-butyllithium (5.1 ml of a 2.5M solution in hexanes) was added to a stirred suspension of 1,3-benzodioxole-5-carboxylic acid (1.0 g) in anhydrous tetrahydrofuran under an inert atmosphere keeping the temperature-below -60° C. The mixture was then stirred at -78° C. for 7 hours and methyl iodide (0.50 g) added and the mixture stirred at room temperature for 18 hours. The mixture was then treated with water and 2N sodium hydroxide. The aqueous phase was washed with ether, acidified and filtered. The solid was washed with hexane and dried to give 4-methyl-1,3-benzodioxole-5-carboxylic acid as a cream solid (0.91 g), m.p. 217°-219° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:12]([CH:15]([CH2:21][CH2:22]Br)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].C(N(CC)CC)C>C(#N)C>[N:12]([CH:15]([CH2:21][CH2:22][NH:1][CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[CH2:10][CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: CCC(N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCNC(CC)C(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C
Yield: 52.5 %

Procedure:
To a solution of tert-butyl 2-amino-butanoate (0.397 g) and ethyl 2-azido-4-bromo-butanoate (0.286 g) in acetonitrile (5 ml) was added triethylamine (0.347 ml). The mixture was heated at 50° C. for 18 h, cooled and evaporated onto silica gel (Merck.7734). The pre-absorbed material was purified by flash column chromatography (Merck. 9385, eluting with cyclohexane:ethyl acetate 6:1) to give the title compound (0.200 g) as a mixture of four diastereomers.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:25](=[O:38])[CH:26]([NH2:37])[CH2:27][C:28]2[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=2[CH3:36])[CH:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH3:13])=[CH:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:37][CH:26]([CH2:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=1[CH3:36])[C:25]([N:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=1)[CH:12]([C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1)[CH3:13])=[O:38]
Reactant: COC(=O)c1ccc(CN(C(=O)C(N)Cc2c(C)cc(O)cc2C)C(C)c2nc(-c3ccccc3)c[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1CC(N)C(=O)N(Cc1ccc(C(=O)O)cc1)C(C)c1nc(-c2ccccc2)c[nH]1
Yield: 87.4 %

Procedure:
A solution of 4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid methyl ester (TFA salt), (0.043 g, 0.067 mmol) in 5 mL of THF was cooled in an ice bath. A cold (5-10° C.) 3M aqueous solution of LiOH (5 mL) was added and the reaction mixture was stirred vigorously while cold. Chilled (5-10° C.) 2M aqueous HCl (7.5 mL) was added dropwise to neutralize the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The resultant aqueous suspension was extracted seven times with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated to afford 0.030 g of 4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid as a white powder. The material was taken up in EtOH and treated with 1M HCl in Et2O. The solution was concentrated and the residue was triturated with CH3CN. A 0.021 g (53%) sample of 4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid was collected as its HCl salt. MS (ES+) (relative intensity): 513.2 (100) (M+1).
Reaction SMILES: S([O:5][C@@H:6]([C@H:9](O)[CH2:10][Cl:11])[CH2:7][Cl:8])(O)(=O)=O.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>CN(C=O)C>[Cl:8][CH2:7][C@@H:6]([OH:5])[C@@H:9]([N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])[CH2:10][Cl:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(O)O[C@H](CCl)[C@H](O)CCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1[C@@H](CCl)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A mixture of 1,4-dichlorobutan-2(S),3(S)-diol sulfate (57.2 mg, 0.258 mmol) and phthalimide potassium salt (51.4 mg, 0.272 mmol) in dry DMF (1.3 mL) was stirred under nitrogen atmosphere at rt for 1 h. Solvent was removed under reduced pressure. The residue was dissolved with dry THF (3 mL). To the resulting solution were added conc. H2SO4 (13 μl) and water (5 μl). After 30 min excess sodium bicarbonate (˜52 mg) was added and the reaction mixture was stirred for 30 min. Filtration through a Celite and silica gel bed and concentration of the filtrate under reduced pressure provided N-(1,4-Dichloro-2(S)-hydroxy-3(R)-butyl)phthalimide (77.8 mg) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][N:12]=[C:11]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:11]([S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[N:12]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A mixture of 7-(3-chloro-propoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.75 mmoles), 3-chloro-benzylbromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 10 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.87 g, 1.66 mmoles).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:17])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[C:14]=2[O:15][CH3:16]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Product: COc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (40 mg, described in Example 105) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (65 mg, 91%). MS (ES): M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 4.20 (s, 3H), 4.76 (d, 1H), 4.89 (d, 1H), 6.87 (dd, J=9.0, 1.7 Hz, 1H), 7.51 (s, 1H), 7.86-7.91 (m, 3H), 7.97 (d, 2H) and 9.01 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([S:38]([N:16]2[CH2:15][CH2:14][N:13]([C:6]3[C:5]([CH3:19])=[C:4]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:26]=4)[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=3)[CH2:18][CH2:17]2)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)C3CCCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and cyclopentylsulfonyl chloride to give 2-(4-(cyclopentylsulfonyl)piperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 1.54-1.58 (m, 2H), 1.67 (s, 2H), 1.80-1.85 (m, 2H), 1.96-1.99 (m, 2H), 2.08 (s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.33 (s, 4H), 3.39 (t, J=4.8 Hz, 4H), 3.69 (t, J=3.6 Hz, 5H), 6.51 (s, 1H), 7.15-7.20 (m, 1H), 7.30 (d, J=11.2 Hz, 1H), 7.52 (s, 1H), 7.78 (s, 1H), 8.37 (s, 1H). Mass Spectrum (ESI) m/e=573.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:11](S(C)(=O)=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].CO>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:11]([O:29][CH3:28])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 85.3 %

Procedure:
2 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine, 0.3 g of sodium methoxide and 20 ml of methanol were added to 120 ml of ethylene glycol dimethyl ether, and the resulting mixture was heated under reflux for 5 hours. The solvent was distilled away under reduced pressure. The residue was washed with water, and then dried to obtain 1.5 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methoxypyrimidine (Compound 18).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].[N-]=[N+]=[N-]>O.CN(C)C=O>[N:1]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCCCl)NC(=O)NC1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CCCN=[N+]=[N-])NC(=O)NC1=O
Reaction time: 21 h

Procedure:
A solution of sodium azide (13 g, 0.2 mol) in water (100 ml) was added to a solution of 5-(3-chloropropyl)-5-methyl-2,4-imidazolidinedione (19.06 g, 0.1 mol) in dimethylformamide (900 ml.) and the mixture was kept at 75° C. for 21 hours. Iodometric determinations of azide ions indicated the consumption of the expected quantities of azide at that time. The mixture was concentrated to a syrup which was redissolved in chloroform (200 ml.), filtered, diluted with chloroform (500 ml.) and water (100 ml.), the chloroform phase was collected after equilibration and combined with four additional chloroform extracts which were dried (MgSO4) and concentrated. Crystalline 5-(3-azidopropyl)-5-methyl-2,4-imidazolidinedione was obtained from chloroform/petroleum ether (17.3 g, 88%), m.p. 104° C. after one recrystallization from the same solvent.