Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.C([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])(=O)C>C(#N)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: CC(=O)OCC(F)(F)F
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 24 h

Procedure:
To a suspension of 4-nitrobenzylamine hydrochloride (10.0 g) and triethylamine (22.2 ml) in acetonitrile (100 ml) was added trifluoroethyl acetate (12.6 ml) at room temperature and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with hexane, to give N-(4-nitrobenzyl)trifluoroacetoamide (12.79 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:14])[O:13][C:11](=O)[CH:10]=[CH:9]1.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1CCCC1=O>[C:2]1([N:1]2[CH:10]([CH2:9][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])[C:11](=[O:13])[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]2=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C=Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(CC1C(=O)N(c2ccccc2)C(=O)N1c1ccccc1)Nc1ccccc1
Reaction time: 1 h

Procedure:
93 g of aniline are added dropwise with cooling at approximately 30° C. to a solution of 98 g of maleic acid anhydride in 300 g of N-methyl pyrrolidone. To complete the formation of the amido acid, the mixture is then stirred for 1 hour at the above-mentioned temperature. 238 g of phenyl isocyanate are then added dropwise at 20° C. and the condensation reaction is carried out with stirring for 1 hour at 50° C., for 2 hours at 90° C., for 2 hours at 120° C. and for 6 hours at 150° C. The reaction product crystallises out on cooling and is recrystallised from acetonitrile and from metahnol. 1,3-Diphenyl-5-(N-phenylaminocarbonylmethyl)-hydantoin is obtained in the form of colourless crystals melting at 214° to 215° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:15][C:16]2=[O:18]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:15][C@H:16]2[OH:18]
Reactant: CC(C)(C)[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@@H]1O[C@@H](O)[C@@H]2[C@H]1C2(C)C
Yield: 98.9 %

Procedure:
15.5 ml of a toluene solution of 20% of diisobutyl aluminum hydride were slowly added at -70° C. to a solution of 2.5 g of the product of Step B in 25 ml of toluene with stirring and the mixture was poured over ice. The mixture was filtered and the filtrate was extracted with ether and was evaporated to dryness under reduced pressure to obtain 2.5 g of (1R,2R,4R,5S) 6,6-dimethyl-4-(2-methyl-prop-2-yl)-3-oxa-bicyclo (3,1,0) hexan-2-ol melting at 126° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[C:15]#[C:16][Si](C)(C)C>CO>[C:15]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:8]=1[F:7])[NH2:12])#[CH:16]
Reactant: C[Si](C)(C)C#Cc1cc(N)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(N)ccc1F
Temperature: 20 °C
Yield: 95.9 %

Procedure:
16 mg of potassium carbonate are added to a solution of 360 mg of 4-fluoro-3-[(trimethylsilyl)ethynyl]aniline in 5 ml of methanol. After stirring over night under argon and at a temperature in the region of 20° C., the medium is concentrated to dryness under reduced pressure, then taken up in 8 ml of water and neutralized with a few drops of hydrochloric acid (1N), and then extracted three times with diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 225 mg of 3-ethynyl-4-fluoroaniline are obtained in the form of a brown oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([CH:52]=O)[CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1)#[N:34]>CCCCCC.C1COCC1>[C:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39](/[CH:52]=[CH:1]/[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[OH:7])[CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1)#[N:34]
Reactant: [Li]CCCC
Reactant: COC(=O)c1ccc(CCC(C=O)CCCCC#N)cc1
Reactant: Oc1ccccc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCCCC#N)cc1
Reaction time: 0.08 h

Procedure:
9.07 ml (14.52 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added dropwise to a suspension of 3.26 g (7.26 mmol) of 2-hydroxyphenyltriphenylphosphonium bromide in 40 ml of dry THF at 0° C., and the mixture is stirred for 5 minutes. Then, at this temperature, a solution of 1.49 g (5.19 mmol) of methyl 4-(7-cyano-3-formylheptyl)benzoate in 10 ml of dry THF is slowly added dropwise. The reaction mixture is stirred at 0° C. for 10 minutes. The cooling is then removed, and the reaction solution is stirred at room temperature for 10 minutes and then mixed with silica gel and concentrated to dryness. The resulting residue is purified directly by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:2→1:5). 1.71 g (75% purity, 3.40 mmol, 65% of theory) of an oil are obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]([CH3:13])([CH3:12])[CH:9]1[O:11][CH2:10]1>CO.O>[N:1]([CH2:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[CH3:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)CN=[N+]=[N-]
Temperature: 0 °C
Yield: 93.8 %

Procedure:
Sodium azide (10 g, 154 mmol) and ammonium chloride (3.7 g, 070 mmol) are added to a solution of 3,3-dimethyl-1,2-epoxybutane (4.26 ml, 35 mmol) in methanol:water (8:1, 315 ml), and the mixture is heated at reflux for 7 hours. The reaction is poured into ice/water (400 ml) and extracted with dichloromethane (3×200 ml). The combined organics are dried (MgSO4), filtered and evaporated to yield a clear oil (4.7 g, 94 %).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35]>CN1C(=O)CCC1.O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCCCOC(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 27.4 %

Procedure:
Triethylamine (1.93 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in NMP (6.0 mL). n-Butyl chloroformate (1.13 g, 3 eq) was added dropwise. The reaction mixture was allowed to come to ambient temperature and stirred for 24 hours. The reaction mixture was diluted with cold water (25 mL) and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2000 mL) followed by recrystallization from acetonitrile to provide 0.35 g of butyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white solid, mp 164-166° C. Anal calcd for C22H31N5O4S: C, 57.25; H, 6.77; N, 15.17. Found: C, 57.13; H, 6.61; N, 15.20.
Reaction SMILES: [C:1](=[O:57])([O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([O:33]CC1C=CC=CC=1)[C@@H:10]([O:41]CC1C=CC=CC=1)[C@@H:9]2[O:49]CC1C=CC=CC=1)[CH3:7])[O:2][CH2:3][CH3:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[C:1](=[O:57])([O:2][CH2:3][CH3:4])[O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([OH:33])[C@@H:10]([OH:41])[C@@H:9]2[OH:49])[CH3:7]
Reactant: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)OC(C)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of ethyl 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl carbonate 12a (76.3 g, 0.09 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.05 mL, 0.48 mmol) and 10% Pd/C (12 mg, 0.01 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/4 to give the title compound 12 as a light yellow solid (38 mg, 60%, HPLC: 89.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 523.2 [M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (m, 1H), 7.09 (s, 2H), 6.83 (m, 2H), 5.59 (d, 1H), 5.13 (d, 1H), 5.02 (d, 1H), 4.93 (m, 1H), 4.14-4.02 (m, 3H), 4.02-3.92 (m, 4H), 3.55 (d, 2H), 3.47-3.37 (m, 2H), 1.31 (m, 6H), 1.19 (t, 3H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C=O>[CH:1]1([O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To 3.9 g of cyclohexanol (1.1 equivalents) put into the presence of 2.12 g of sodium hydride (1.5 equivalents) under stirring for 10 min, is added a solution of 5 g of 4-fluoronitrobenzene in 75 mL of dimethylformamide. The whole is heated to 60° C. for 5 hrs. After returning to room temperature, the medium is hydrolyzed and the reaction crude product is extracted with ethyl acetate several times. The organic phases are dried on magnesium sulfate, filtered and evaporated under reduced pressure. With a silica gel chromatography of the residue (cyclohexane and then cyclohexane/ethyl acetate: 98/2 and 90/10) 6.06 g of the desired product are able to be isolated.
Reaction SMILES: N1CC[CH2:3][CH2:2]1.C(O)(=O)C.[CH3:10][CH:11]([N:13]1[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)[CH3:12].[F:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>C(O)C>[CH3:10][CH:11]([N:13]1[C:17]([CH3:18])=[C:16]([CH:23]([C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[F:20])[O:24][CH2:2][CH3:3])[C:15](=[O:19])[NH:14]1)[CH3:12]
Reactant: Cc1cc(=O)[nH]n1C(C)C
Reactant: COc1ccc(C=O)c(F)c1
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(c1ccc(OC)cc1F)c1c(C)n(C(C)C)[nH]c1=O
Temperature: 50 °C

Procedure:
Pyrrolidine (21 ml; 0.257 mol) and acetic acid (22 ml; 0.385 mol) are added to a mixture of 1,2-dihydro-1-(1-methylethyl)-5-methyl-3H-pyrazol-3-one (180 g; 1.28 mol) and 2-fluoro-4-methoxybenzaldehyde (198 g; 1.28 mol) in ethanol (2.7 L). The suspension is heated to about 50° C. for about 67 h. The reaction mixture is then cooled to approx. 17° C. and filtered. The product is washed with diisopropyl ether (500 ml) and subsequently refluxed with THF (2.5 L). The obtained solution is filtered over a pad of Celite and charcoal. The filtrate is concentrated in vacuo and water (2 L) is added to the suspension which is cooled and filtered. The colourless crystals are dried at 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:18]([O:17][C:15](=[O:16])[NH:14][C@@H:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH2:9]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To an ice cold solution of (S)-3-(2-amino-phenylamino)-2-tert-butoxycarbonylamino-propionic acid (4 g, 13.54 mmol) in DMF (40 mL) was added EDCI.HCl (2.86 g, 14.89 mmol), HOBT (2.01 g, 14.89 mmol) and DIPEA (7.19 mL, 40.63 mmol). The resulting mixture was stirred for 16 h at RT. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated and the resulting material was purified by silica gel chromatography using to afford the title compound (2.9 g, 77%) as an off white solid. LC-MS: 278 (M+H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:38][N:39]([CH3:44])[CH2:40][C:41](O)=[O:42].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:41](=[O:42])[CH2:40][N:39]([CH3:44])[CH3:38])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)CC(=O)O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (25.1 μl ) was added, N,N-dimethylglycine hydrochloride (16.7 mg) and WSC.HCl (23 mg) were added thereto and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC. The obtained compound was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: C1(C[N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)C=CC=CC=1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH2:11]1[C@@H:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[CH2:14][CH2:13][O:12]1
Reactant: c1ccc(CN2CCN3CCOC[C@@H]3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C1CN2CCOC[C@@H]2CN1
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To (9aS)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (1.80 g, 7.70 mmol) in MeOH (30 mL) was added 6N HCl (3.00 mL, 18.0 mmol) followed by Pd on carbon (0.186 g, 10% w/w with starting oxazine). The mixture was placed under H2 (1 atm) overnight. The mixture was filtered through Celite® and washed thoroughly with MeOH to provide the title compound of step G (0.851 g, 4.00 mmol, 52%). 1H NMR (400 MHz, CD3OD) δ ppm 3.26-3.35 (m, 1H), 3.38-3.47 (m, 2H), 3.52-3.57 (m, 1H), 3.65-3.69 (m, 1H), 3.71-3.82 (m, 4H), 3.92-4.00 (m, 1H), 4.02-4.13 (m, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]3[S:9][C:8]([NH2:11])=[N:7][C:6]=3[CH:5]=[C:4]([CH3:12])[C:3]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: COc1c(C)cc2nc(N)sc2c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1

Procedure:
The mixture of 7-bromo-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8A) (1.72 g, 6.32 mmol), 4-chlorophenyl boronic acid (1.2 g, 7.67 mmol), K2CO3 (2.63 g, 18.9 mmol), Pd(PPh3)4 (364 mg, 0.315 mmol) in DME (8 ml) and H2O (4 ml) was reacted in microwave at 110° C. for 1 h. Then 4-chlorophenyl boronic acid (100 mg, 0.64 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol) were added and reacted in microwave at 110° C. for 0.5 h and 120° C. for 20 min. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C15H13ClN2OS: 305.0 (M+H+). Found: 305.1 (M+H+).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].O.[NH2:22][NH2:23]>CCO>[NH2:2][C:1]1[NH:23][N:22]=[C:7]([NH:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#Cc1cccc(N)c1
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(Nc2n[nH]c(N)c2C(N)=O)c1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 3-Aminobenzonitrile (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((3-cyanophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[CH3:61][NH:62][CH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:62]([CH3:61])[CH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNC1CCOCC1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CN(C1CCOCC1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 416.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:15]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[NH:1]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH2:15]
Reactant: O=N[O-]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc2ccccc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-amino-2-naphthoic acid (15 g, 66.8 mmol) in conc. HCl (100 ml) and water (100 ml) at 0° C. was added NaNO2 (9.22 g, 69 mmol) in 1 g portions while maintaing the reaction temperature below 0° C. After 30 min below 0° C., SnCl2.H2O (75 g) was added in portions over 20 min. The ice bath was removed and stirred at ambient temperature for 1 h. Reaction was filtered and the filter cake washed with water and air dried. The crude material containing tin (II) salts was used as is and gave a mp>300° C.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:14][OH:15]>C(O)C>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:13]([NH:12][CH2:11][C@H:9]([OH:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][OH:15])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Yield: 75 %

Procedure:
A mixture of (2S)-2-(phenoxymethyl)oxirane (2.30 g), (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (3.0 g) and ethanol (30 ml) was heated under reflux for 18 hours. The reaction mixture was evaporated in vacuo. The residue was triturated with ethyl acetate to give (2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propanol (3.97 g) as a pale yellow powder. This powder was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)c3ccccc3)CC2)CC1
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) and triethylamine (0.22 ml) in methylene chloride (30 ml) is added benzoyl chloride (0.19 ml) at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is washed with water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol=20:1) to give the desired compound (610 mg).