Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CO.O>[C:30]([S:32][C@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:33])[CH3:31]
Reactant: CC([O-])=S
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)S[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of 0.7 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 10 ml of methanol is added a solution of 0.25 g of potassium thioacetate in 2 ml of water. The mixture is stirred for 30 minutes at 55°-60° C. Methanol is distilled off under reduced pressure. To the residue is added ethyl acetate, followed by washing with water, drying and concentration under reduced pressure. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.195 g of (3R,4R)-4-acetylthio-3-tritylamino-2-oxoazetidine
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:32]C)=[C:7]([C:9]2[N:18]=[C:17]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1)=O.[NH2:34][NH:35][C:36]([NH2:38])=[S:37]>C(O)C>[NH2:38][C:36]1[S:37][C:1]([C:3]2[CH:4]=[CH:5][C:6]([OH:32])=[C:7]([C:9]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:8]=2)=[N:34][N:35]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(C=O)cc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Solvent: CCO
Product: Nc1nnc(-c2ccc(O)c(-c3nc(N[C@H]4CCNC4)c4ccccc4n3)c2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 3-(2-(5-formyl-2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.160 g, 0.357 mmol) was dissolved in ethanol (2 mL) and thiosemicarbazide (0.033 g, 0.362 mmol) was added and the solution was stirred at room temperature for 16 h. The solid was filtered off and washed with ethanol (2×1 mL). The solid was suspended in water (16 mL) and ferric chloride (0.267 g, 1.00 mmol) was added and the solution was heated at 60° C. for 16 h. A further portion of ferric chloride (0.267 g, 1.00 mmol) was added and the solution heated at 90° C. for 2.5 h. The reaction mixture was partitioned between water (20 mL) and dichloromethane (20 mL), but the bright yellow product was visibly in the aqueous phase so the aqueous phase was concentrated in vacuo and the residue was purified by ion exchange chromatography on SCX-2 (solute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by HPLC. Semi-prep HPLC was performed on an Agilent 1200 series with a Phenomex Gemini 250 mm×10 mm i.d. column at a temperature of 20 C and a flow rate of 5 mL/min using a gradient of 10%-100% acetonitrile in water over 30 mins.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>CC#N>[CH3:6][CH:5]([CH3:7])[C:4](=[O:8])[CH2:3][CH2:2][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: CC(C)C(=O)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)C(=O)CCNc1ccccc1

Procedure:
A suspension of the crude 1-chloro-4-methylpentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHCO3 (210 g, 2.5 mol) in CH3CN (1000 mL) was heated at reflux overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with CH2Cl2, washed with 10% HCl solution (100 mL) and brine, dried over Na2SO4, filtered and concentrated to give the crude 4-methyl-1-(phenylamino)-pentan-3-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33]2>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:34]1[CH2:33][C:32]2[C:36](=[CH:37][CH:38]=[C:30]([Br:29])[CH:31]=2)[CH2:35]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2c(c1)CNC2
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
Coupling of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (5.0 g, 13.4 mmol) (Preparation B9) and 5-bromo-2,3-dihydro-1H-isoindole (Preparation C20) was completed according to method A4, using CH2Cl2 as the reaction solvent to give the title compound (8.34 g) as a beige solid.
Reaction SMILES: [Na].[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)([O:4]CC)=O.Cl.[C:15]([NH2:18])(=[NH:17])[CH3:16]>C(O)C>[CH3:16][C:15]1[NH:18][C:2](=[O:4])[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:17]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc2c(c(=O)[nH]1)CCCC2
Temperature: 25 °C

Procedure:
To 50 mL of absolute ethanol under a nitrogen atmosphere was added 5.65 g of sodium metal. After all the sodium had reacted, 20.15 g of 2-carboethoxycyclohexanone was added followed by 14.50 g of acetamidine hydrochloride. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. Successive crops of solid were collected by concentration of the mother liquors (13.1 g, 65%): 1H NMR (DMSO-d6, 300 MHz) δ 12.18 (s, 1H), 2.22 (m, 2H), 2.15 (m, 2H), 2.10 (s, 3H), 1.65 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[NH:43][C:44]([NH:46][CH:47]1[CH2:49][CH2:48]1)=[O:45])[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[C:20]([C:23]#[N:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH:40]=[CH:41][C:42]=1[NH:43][C:44]([NH:46][CH:47]1[CH2:49][CH2:48]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCC1CCNCC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
After adding trifluoroacetic acid (2.5 ml) to tert-butyl 4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (501 mg, 0.846 mmol) at room temperature, the mixture was stirred for 1 hour. The reaction solution was diluted with water (35 ml) while cooling in an ice water bath, and then sodium bicarbonate (3.5 g) was gradually added for neutralization and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the precipitated crystals were filtered out and blow-dried to obtain the title compound (414.4 mg, 0.842 mmol, 99.6%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([O:38]C)=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>O.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccccc1CN(C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To the solution of compound 2d (100 mg, 0.17 mmol) in H2O (2 mL) and MeOH (10 mL) was added aqueous NaOH (33 mg, 0.84 mmol). The resulting mixture was heated to reflux for 2 hr. Then the mixture was cooled to rt and acidified to pH=3 with 3.5N aqueous HCl, concentrated in vacuo to remove the volatile solvent. The resulting mixture was extracted with EA (2×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4, concentrated in vacuo to give compound 2e as a white solid (80 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-])=O)[CH:12]=3)[N:10]=2)[N:7]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH:12]=3)[NH2:18])[N:10]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1N
Temperature: 80 °C
Yield: 80.6 %

Procedure:
To a mixture of 6-chloro-3-methyl-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (2.00 g, 6.60 mmol) in ethanol (100 mL) and water (25 mL) containing AcOH (39.6 mmol) is added iron (1.84 g, 33.0 mmol). The mixture is heated at 80° C. for 6 hours, then cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude is purified via chromatography (hexanes to EtOAc) to afford the title compound (1.45 g, 80%) as a yellow solid: Rf 0.52 (EtOAc); LCMS (m/z)=273.3, 275.3 [M+H]+, tR=1.79 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNCC1
Reactant: COc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: COc1cccc(N2CCCCC2)c1
Temperature: 105 °C

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 4.72 g of piperidine in 20 ml of o-xylene, a solution of 7.99 g of m-bromoanisole in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/m-bromoanisole=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 105° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate, concentrated, and then distilled to give N-(3-methoxyphenyl)piperidine. The yield of the isolated compound was 95% by mole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Fc1cccc(CBr)c1
Product: CCOC(=O)c1ccn(Cc2cccc(F)c2)c1C

Procedure:
Prepared in analogy to that of Example 5(a) from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-fluorobenzyl bromide. The title compound, ESI MS (m/z): 262 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][C:20]=2[CH3:29])[CH2:3]1
Reactant: Cc1cnc2ccccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cnc2ccccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.175 g, 0.754 mmol), 4-chloro-3-methylquinoline (0.134 g, 0.754 mmol), cesium carbonate (0.492 g, 1.5 mmol), Pd2(dba)3 (0.069 g, 0.075 mmol) and (±) BINAP (0.070 g, 0.113 mmol) in toluene (3 mL). After purification by HPLC 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-3-methylquinoline was obtained. 1H NMR (400 MHz, MeOH) δ ppm 8.82 (1H, s), 8.07 (1H, d, J=8.2 Hz), 7.94 (1H, d, J=8.2 Hz), 7.73 (1H, m), 7.55 (1H, t, J=7.6 Hz), 7.10 (1H, d, J=8.2 Hz), 6.39 (1H, dd, J=8.2, 2.0 Hz), 5.59 (1H, s), 3.79 (1H, m), 3.76 (1H, m), 3.68 (4H, m), 2.89 (4H, m), 2.37 (3H, s), 1.50 (3H, s), 1.46 (3H, s). Mass Spectrum (ESI) m/e=375 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:22]1[CH2:31][CH:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][C:37]=1[O:45][C:46]([F:47])([F:48])[F:49])(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1ccc(CO)cc1C1(N2CC(O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 55.9 %

Procedure:
With 3.09 g of the compound obtained in Step 204-5 and 2.05 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.68 g of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccccc1OC
Reactant: Oc1ccc(S)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccccc1OC
Yield: 89 %

Procedure:
Ethyl(2-methoxyphenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(2-methoxyphenyl)acetate (24 g, 87.5 mmol) and 4-mercaptophenol (11.0 g, 87.5 mmol); 24.9 g amber colored oil. Yield 89%; MS: 320 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].[CH3:14][Mg]Br>O1CCCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[CH3:14]
Reactant: C[Mg]Br
Reactant: Cc1nc2c(Br)c(C=O)ccc2s1
Solvent: C1CCOC1
Product: Cc1nc2c(Br)c(C(C)O)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-methyl-1,3-benzothiazole-5-carbaldehyde (1.70 g, 6.64 mmol) in tetrahydrofuran (30 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (9.48 mL) at 0° C. The reaction was stirred at room temperature for 30 minutes, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude residue was used directly in next step (1.81 g, 100%). LCMS calculated for C10H11BrNOS(M+H)+: m/z=272.0; found: 271.9.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15](C(=O)C(F)(F)F)[CH2:16][CH2:17][C:11]=2[C:10]=1[S:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])#[N:8].O.C(Cl)Cl>CO>[C:9]([O:2][C:1]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([S:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[C:9]([C:7]#[N:8])[CH:25]=[CH:24][C:12]=2[CH2:13][CH2:14]1)=[O:4])([CH3:25])([CH3:10])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Add potassium carbonate (4.13 g, 30 mmol) to a stirred solution of 7-cyano-6-dimethylcarbamoylsulfanyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (740 mg, 2.0 mmol) in methanol (40 mL)/water (15 mL) and stir for 1.5 h. Add DCM (10 mL), di-text-butyl dicarbonate (480 mg, 2.2 mmol) and stir at ambient temperature for 3 days. Concentrate in vacuo and dilute with DCM, wash with water and extract with DCM. Combine the organic layers, wash with brine, dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc:heptane (0:1 to 1:1) to give the title compound as a colourless foam (370 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 3.69-3.48 (m, 4H), 3.26-3.02 (m, 10H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:30])[NH:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:6]=2[CH:5]=[C:4]([NH:31][C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])=[O:33])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C([SiH](CC)CC)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[C:7]2[C:8]([O:30][CH:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:31][C:32]([NH:34][C@@H:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36])=[O:33])[N:3]=1
Reactant: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: IC1CCOCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-1-(4-methyl-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.090 mmol), Cs2CO3 (91 mg, 0.279 mmol), and 4-iodotetrahydro-2H-pyran (25 μL, 0.209 mmol) in DMF (1 mL) was stirred at room temperature for 18 h. The reaction was quenched with MeOH and concentrated in vacuo. The residue was dissolved in TFA (2 mL), charged with triethylsilane (0.02 mL, 0.125 mmol), and stirred at room temperature for 2 h. The reaction mixture was diluted with DMSO (4 mL) and purified by mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS—HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(4-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C21H25N5O3 [M+1]+ 396. found 396. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.12 (br s, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 7.16 (br s, 1H), 4.95 (m, 1H), 4.84 (quintuplet, J=7.1 Hz, 1H), 3.84 (m, 2H), 3.52 (m, 2H), 2.59 (s, 3H), 2.06 (m, 1H), 1.71 (m, 1H), 1.39 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1C[O:27]CC1.[OH-].[Na+].OO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:12]([OH:27])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C1=C(CCCc2ccccc2)CCN(Cc2ccccc2)C1
Agent: B
Agent: OO
Agent: [Na+]
Product: O[C@@H]1CN(Cc2ccccc2)CC[C@H]1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.590 g (2.02 mmol) of 1-benzyl-4-(3-phenylpropyl)-1,2,3,6-tetrahydropyridine and 4.4 mL of a 1M solution of BH3.THF in THF in 5 mL of THF was heated under reflux for 1 h. The mixture was cooled to rt, and 5 mL 1N NaOH and 5 mL 30% H2O2 were added and stirring was continued for 0.5 h. The mixture was partitioned between 75 mL of ether and 25 mL of H2O. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue and 2 mL of ethanolamine were combined in 2 mL of methanol and heated under reflux for 1 h. The mixture was cooled to rt and partititioned between 100 mL of ether and 50 mL of sat'd NaCl solution. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 2:1) to give 1-benzyl (trans)-3-hydroxy-4-(3-phenylpropyl)piperidine. Removal of the benzyl protecting group was achieved under standard conditions.
Reaction SMILES: [N:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([NH:13][C:14]3[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=3[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:17])=[O:12])=[C:9]([O:32][CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[NH:13][C:11](=[O:12])[C:10]2[CH:30]=[CH:31][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCOCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)c1ccc(N2CCOCC2)cc1OC1CCNCC1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
The 2-[4-(morpholin-4-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (164 mg, 0.26 mmol) was dissolved in TFA (3 mL). After 5 minutes, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (100 mL) and washed with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product (138 mg, 0.26 mmol, 100%).