Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (2RS,3SR)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (7.0 g), methyl 3-mercaptopropionate (30.8 ml) and 28% sodium methylate-methanol solution (19.6 ml) in methanol (210 ml) was refluxed for 2 hours. 28% Sodium methylate methanolic solution (9.8 ml) was added to the resultant solution and refluxed for 1 hour. Thereafter, methyl 3-mercaptopropionate (4 ml) was added to the resultant solution and refluxed for 2 hours. After ice-cooling, the reaction mixture was diluted with water (100 ml) and neutralized with 5% aqueous phosphate solution, and extracted with methylene chloride (200 ml×2). The extract was dried over anhydrous sodium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (4×50cm), eluting with ethyl acetate-hexane (3:1). The collected fractions of the object compound were concentrated and ethyl ether was added to the residue to obtain (2RS,3 RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2butanol (5.5 g) as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2CCN1CCCC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.665 mmol) in DMF (10 mL) was treated with NaH (213 mg, 5.33 mmol, 60% wt in mineral oil) at 0° C., resulting in a bright orange suspension. The mixture was stirred for 10 minutes. 2-chloroethyl-pyrrolidine hydrochloride (566 mg, 3.33 mmol) was then added, and the reaction turned into a bright red suspension. The reaction was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was then diluted with water (20 mL), transferred to a separatory funnel, and extracted into EtOAc (2×15 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel using CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a solid (330 mg, 72%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.3 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.58-3.55 (m, 4H), 2.63 (t, J=6.9 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.63 (m, 4H); ESI-MS (m/z, %): 278 (MH+, 100), 98 (20).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C1COCC1.P(OCC)(OCC)([S-])=[S:25]>O>[C:1]([C:3]1[C:4]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:25])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(CC2CCC2)cc1C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(CC2CCC2)cc1C
Temperature: 80 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00 g, 20.6 mmol, 1.00 equiv) in a solvent mixture of THF and H2O (50 mL/25 mL). O,O′-diethyl dithiophosphate (15.0 g, 80.5 mmol, 4.00 equiv) was added to the reaction flask. The resulting solution was stirred at 80° C. for 48 h (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the reaction was carefully quenched with 50 mL of brine. The mixture was extracted with 3×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 1.20 g (21%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:37][C:2]2[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=3)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:29])([F:30])[F:31])[N:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: NC1CCCC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NC2CCCC2)cc(F)c1NS(C)(=O)=O
Yield: 8 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (30 mg, 0.057 mmol) was reacted with cyclopentylamine (500 μl) as in example 65 to give the title compound (2.5 mg, 8%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:32])[NH2:31])[CH:25]=3)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=[NH:6])[CH3:5]>Cl.C(#N)C>[ClH:1].[ClH:1].[ClH:1].[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:31])[NH2:32])[CH:25]=3)=[CH:18][CH:19]=2)[CH2:9][CH2:8]1)(=[NH:6])[CH3:5]
Reactant: CCOC(=O)CCCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Agent: Cl
Solvent: CC#N
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)CCCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 183 %

Procedure:
Ethyl 4-[N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]amino]butyrate trihydrochloride (572 mg) was dissolved in 2M hydrochloric acid (20 ml) and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 18% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in 18% aqueous acetonitrile (20 ml) was added 1M hydrochloric acid (1.0 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 20 ml) was lyophilized to give the title compound (333 mg, yield 61%) as a pale brown amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH:9]([OH:12])[C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)C(=O)CC(C)(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc2c(c1)C(O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of 5,6,7,8-tetrahydro-3,7,7-trimethylquinoline-5-one (240 mg, 1.3 mmol) in MeOH (6.5 mL) was cooled to 0° C. under Argon and treated with NaBH4 (48 mg, 1.3 mmol). The reaction was stirred over 14 h and allowed to warm to ambient temperature. The solvent was removed under reduced pressure and the crude oil that was chromatographed on a silica gel column packed in 95:5 EtOAc:hexanes and eluted with same. The appropriate fractions were combined and the solvent was removed under reduced pressure to give 5,6,7,8-tetrahydro-3,7,7-trimethylquinoline-5-ol.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1([O:25][C:26]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([O:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:26]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:25])[CH2:17][CH2:18]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: c1ccc2c(OCC3CCNCC3)cccc2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)CC1
Temperature: 50 °C

Procedure:
A solution of 2.75 g (11.4 mmol) of 4-[(1-naphthalenyloxy)methyl]piperidine, prepared in Step 7.2, and 2.56 g (11.4 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared in accordance with Example 1.1, in 80 ml of toluene is heated at 50° C. overnight. It is evaporated to dryness and the residue is taken up in a mixture of water, dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase is decanted, dried over sodium sulfate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 50/50 mixture of cyclohexane and dichloromethane and then with dichloromethane and with a 95/5 mixture of dichloromethane and ethyl acetate. This gives 2.05 g of product in oil form, which is used as it is in the following step.
Reaction SMILES: [CH3:1][C:2]([CH3:57])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:54])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:53])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)[CH3:45])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:56])[CH3:55])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>ClCCl>[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:52])[NH:43][C@@H:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH3:45])[CH2:22][CH2:21][C@:20]3([CH3:53])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:54])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:57])[C:3]([OH:5])=[O:4])[C:15]3([CH3:55])[CH3:56])[C:24]=12)([CH3:38])[CH3:39].[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccn2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(((R)-1-(pyridin-2-yl)ethyl)amino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (470 mg, 0.599 mmol) in dichloromethane (10 mL) stirred at rt was added TFA (5 mL). The reaction mixture was stirred at rt for 2 h. Then, it was evaporated in vacuo to get crude product. This material was purified by preparative-HPLC to provide the title compound trifluoroacetic acid salt (225 mg, 0.267 mmol, 44.6%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=9.23 (d, J=6.8 Hz, 1H), 8.75 (d, J=3.5 Hz, 1H), 8.32 (t, J=7.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.84-7.69 (m, 1H), 6.77 (d, J=15.8 Hz, 1H), 5.89 (d, J=15.8 Hz, 1H), 5.49-5.21 (m, 1H), 4.50 (dd, J=5.4, 10.7 Hz, 1H), 3.32-3.05 (m, 1H), 2.78-2.49 (m, 3H), 2.33-2.01 (m, 3H), 2.03-0.63 (m, 47H); LC/MS: m/z calculated 728.5. Found 729.4 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]([CH3:31])[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:19]1[CH:18]=[C:17]([C:32](=S)N)[CH:16]=[CH:15][C:14]=1[S:13]2>C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]([CH3:31])[CH2:25][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:19]1[CH:18]=[C:17]([C:32]3[NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[N:1]=3)[CH:16]=[CH:15][C:14]=1[S:13]2
Reactant: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C

Procedure:
1,2-Diaminocyclohexane (15.78 cc) is added to an ethanolic solution (70 cc) of 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (5.20 g). The mixture is heated in an autoclave to 150° C. for 17 hours. After cooling, the reaction mixture is diluted with ethyl acetate (250 cc) and washed with j distilled water (5×250 cc). The organic phase is extracted with normal hydrochloric acid solution (300 cc). After separation of the organic phase when settling has taken place, the acidic aqueous phase is alkalinized with concentrated caustic soda and extracted with ethyl acetate (200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulpate, filtered and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is chromatographed on a column (height: 52 cm; diameter: 2.5 cm) of silica gel (0.2-0.06 mm), eluting with pure ethyl acetate (2 liters) and collecting 120-cc fractions. The first liter is discarded, and fractions 4 to 7 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 7-chloro-2-(3a, 4, 5, 6, 7, 7a-hexahydro-1H-benzimidazol-2 -yl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]phenothiazine (0.72 g) in the form of a yellow solid, m.p. 120° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.66 (m, 6 H) 1.72 (m, 4 H) 1.92-1.99 (m, 5 H) 2.15 (s, 3 H) 2.76 (d, J=11.4 Hz, 2 H) 3.71 (m, 1 H) 4.04 (t, J=14.2 Hz, 2 H) 4.78 (t, J=7.8 Hz, 1 H) 7.77 (s, 4 H) 8.03 (d, J=7.6 Hz, 1 H) 8.27 (s, 1 H) 9.67 (s, 1 H). Melting point: 234-2350C. [M+H] calc'd for C26H33F2N7O2, 514; found 514.
Reaction SMILES: [NH3:1].[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14](Cl)[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]>N.CC(O)C>[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14]([NH2:1])[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 7-(3-tert-butyl-8-chloroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline (92.5 mg, 0.224 mmol) in NH3/i-PrOH (2M, 5 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 21 h. After excess NH3 and i-PrOH were removed in vacuo, the residue was suspended between CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine (3×25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH (7N NH3):CH2Cl2 1%→2%], affording the title compound, as a fine yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 9H), 5.18 (s, —NH2), 7.08 (d, J=4.8 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 3H), 7.90-7.97 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.42-8.44 (m, 1H); MS (ES+): m/z 394.1 (25) [MH+]; HPLC: tR=2.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35].CO>N1C=CC=CC=1>[CH2:32]([S:36]([NH:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:19][CH:20]=3)[C:5]2=[N:6][CH:7]=1)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCc1nc2c(C)c(N)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCS(=O)(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a mixture of 6-amino-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (80 mg, 0.15 mmol) in pyridine (0.5 mL) at 0° C. was added butylsulfonyl chloride (0.02 mL, 0.15 mmol). The mixture was stirred for 1 h, then 1 mL of MeOH was added and the mixture was concentrated. Purification (SiO2, 5% MeOH-EtOAc) gave 50 mg of 6-[(Butylsulfonyl)amino]-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a solid.
Reaction SMILES: F.C([Si](C)(C)[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:40])[N:16]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[C:17]2[N:18]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[N:19]=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:10][CH2:9]1)(C)(C)C>C(OC(C)=O)(C)C.[Cl-].[Na+].O.C(Cl)Cl>[Cl:39][C:35]1[CH:34]=[C:33]([N:16]([C:17]2[N:18]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[N:19]=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[C:15]([NH:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([OH:7])[CH2:13][CH2:12]2)=[O:40])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)N(c2cccc(Cl)c2)c2c3ccccc3nn2-c2ccc(Cl)cc2)CC1
Agent: F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H]1CC[C@H](O)CC1)N(c1cccc(Cl)c1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrofluoric acid (48%, 200 μl, 16 μmol) was added to a solution of trans-3-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1-(3-chloro-phenyl)-1-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-urea (10 mg, 16 μmol) in CH3CN/CH2Cl2 1/1 (400 μl). The reaction mixture was stirred for 4 h at ambient temperature, diluted with CH2Cl2 (5 ml) and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (2 mg, 4 μmol; 25%) as brown solid. MS: m/e=495.5 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Sn].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1cc(S(=O)(=O)Cl)ccc1OCC(=O)OCC
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CCCc1cc(S)ccc1OCC(=O)OCC

Procedure:
A mixture of (4-chlorosulfonyl-2-propyl-phenoxy)-acetic acid ethyl ester (1.12 g, 3.5 mmol), tin powder (2.1 g) and HCl (4.0 M in dioxane, 4.4 mL) in ethanol (4.4 mL) was refluxed for 4 h, the mixture was poured into ice, extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated to give the title compound, which was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[F:27][C:28]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:34]([C:33]1[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:35])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3)c2cc1OC
Reactant: O=C(O)c1cccnc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5F)ccc4c3)c2cc1OC

Procedure:
6-(6,7-Dimethoxy-4-quinolyloxy)-2-naphthylamine (69.2 mg, 0.2 mmol, Example 1c), 2-fluoropyridine-3-carboxylic acid (33.8 mg, 0.24 mmol, Maybridge), DIEA (31 mg, 0.24 mmol, Aldrich) and TBTU (91.2 mg, 0.24 mmol, Advanced ChemTech) were stirred in 6 mL of dry DMF at RT for 24 h. The solution was diluted with 50 mL of EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 470.0 (M+1). Mass Calc'd for C27H20FN3O4: 469.14.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(C(N)=O)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([NH2:33])=[O:32])=[CH:34][CH:35]=3)=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(C(N)=O)cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NC(=O)c1ccc(Br)cc1
Product: NC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 83 %

Procedure:
4-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (47 mg, 0.071 mmol) and 4-bromobenzamide following General Procedure A. Flash chromatography (30-50% EtOAc/hexanes) yielded the title compound as a white solid (29 mg, 83%): 1H NMR (CDCl3, 600 MHz) δ 7.67 (d, 2H, J=7.8 Hz), 7.57 (d, 2H, J=7.8 Hz), 7.38 (s, 1H), 7.25-7.24 (m, 2H), 7.15-7.14 (m, 3H), 6.16 (br s, 2H), 4.84 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.93-1.87 (m, 2H), 1.58-1.56 (m, 2H), 1.46-1.34 (m, 6H), 0.88 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 169.5, 143.6, 132.8, 129.9, 129.5, 129.2, 129.1, 129.0, 128.3, 127.7, 126.4, 125.0, 69.4, 37.3, 36.8, 32.2, 30.0, 26.6, 26.0, 19.1, −4.1, −4.2.