Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:30][CH:29]=[CH:28][CH2:27]1.C1(N(C)C2CCCCC2)CCCCC1>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:30]3[CH2:29][CH:28]=[CH:27][O:26]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:29]3[CH:28]=[CH:27][O:26][CH2:30]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: C1=CCOC1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2ncccc2C2C=COC2)cc1)c1nc2ccccc2[nH]1
Product: O=C(c1ccc(Oc2ncccc2C2CC=CO2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (1.522 g, 3.86 mmol), 2,5-dihydrofuran (1.400 mL, 18.98 mmol, Aldrich), N-cyclohexyl-N-methylcyclohexanamine (1.600 mL, 7.54 mmol, Aldrich) and bis(tri-tert-butylphosphine)palladium (0) (0.194 g, 0.380 mmol, Strem) in dioxane (10 mL) was sealed in a microwave vessel under an atmosphere of argon and heated thermally at 80° C. for 6 h. The reaction was diluted with EtOAc and the mixture was extracted with water (1×) and brine (1×). The organic mixture was evaporated onto silica gel and purified by flash chromatography (Isco (120 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give 650 mg of (1H-benzo[d]imidazol-2-yl)(4-(3-(2,3-dihydrofuran-2-yl)pyridin-2-yloxy)phenyl)methanone and 325 mg of (1H-benzo[d]imidazol-2-yl)(4-(3-(2,3-dihydro furan-3-yl)pyridin-2-yloxy)phenyl)methanone.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([CH3:23])[CH:33]=[CH:32][C:27]=4[N:28]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: Cc1ccc2nc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)sc2c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 34 mg (28%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.68 (br s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.0, 1.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.13-7.06 (m, 2H), 3.84-3.80 (m, 2H), 2.47-2.41 (m, 5H), 1.66-1.59 (m, 2H).
Reaction SMILES: BrC1C=C[C:5]([C:8]#[C:9][C:10]2([CH2:27]CCCC)[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4](F)[CH:3]=1.C(C1(C=O)CCC(C2CCC(CCCCC)CC2)CC1)CCCC.[Br-].Br[C:59]1[CH:84]=[CH:83][C:62]([CH2:63][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:61]([F:85])[CH:60]=1.BrBr.[C:88]([C:90]1([CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:95][CH2:94][CH:93]([CH:96]2[CH2:101][CH2:100][CH:99]([CH2:102][CH2:103][CH2:104][CH2:105][CH3:106])[CH2:98][CH2:97]2)[CH2:92][CH2:91]1)#[CH:89]>N1CCCC1>[CH2:107]([C:90]1([C:88]#[C:89][C:59]2[CH:84]=[CH:83][C:62]([C:63]#[C:27][C:10]3([CH2:9][CH2:8][CH2:5][CH2:4][CH3:3])[CH2:15][CH2:14][CH:13]([CH:16]4[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[C:61]([F:85])[CH:60]=2)[CH2:91][CH2:92][CH:93]([CH:96]2[CH2:101][CH2:100][CH:99]([CH2:102][CH2:103][CH2:104][CH2:105][CH3:106])[CH2:98][CH2:97]2)[CH2:94][CH2:95]1)[CH2:108][CH2:109][CH2:110][CH3:111]
Reactant: Fc1cc(Br)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC1CCC(C2CCC(C#Cc3ccc(Br)cc3F)(CCCCC)CC2)CC1
Reactant: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Agent: BrBr
Agent: CCCCCC1CCC(C2CCC(C=O)(CCCCC)CC2)CC1
Agent: [Br-]
Solvent: C1CCNC1
Product: CCCCCC1CCC(C2CCC(C#Cc3ccc(C#CC4(CCCCC)CCC(C5CCC(CCCCC)CC5)CC4)c(F)c3)(CCCCC)CC2)CC1

Procedure:
0.908 g of 4-(4-bromo-2-fluorophenylethynyl)-4,4′-dipentylbicyclohexyl (obtainable by Wittig reaction of 4,4′-dipentylbicyclohexyl-4-carbaldehyde with 4-bromo-2-fluorobenzyltriphenylphosphonium bromide, addition of bromine onto the resultant alkene and subsequent dehydrobromination using a base), 0.715 g of 4-ethynyl-4,4′-dipentylbicyclohexyl and 0.104 g of tetrakis-(triphenylphosphine)palladium(0) are stirred overnight at 80° C. in 5 ml of pyrrolidine. Conventional work-up gives 4-[4-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-2-fluorophenylethynyl]-4,4′-dipentylbicyclohexyl (C 177 I).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[CH:18](=[O:20])[CH3:19]>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[CH:18]([OH:20])[CH3:19]
Reactant: CC=O
Reactant: Clc1cc(Cl)cc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (3 mL, 6 mmol) in THF (5 mL) was added 1,3,5-trichlorobenzene (0.91 g, 5.0 mmol) in THF (3 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of acetaldehyde (0.33 g, 7.5 mmol) in THF (3 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 1.62 (d, J=6.8 Hz, 3H), 2.76 (d, J=9.9 Hz, 1H, —OH), 5.55 (m, 1H), 7.32 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:32]1COCC1.[H-].[Na+].CI>ClCCl.CO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]([CH3:32])[CH2:23][C:24]3[CH:29]=[N:28][CH:27]=[N:26][CH:25]=3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: ClCCl
Product: CN(Cc1cncnc1)C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrimidin-5-ylmethyl)acrylamide (0.05 g, 1.0 eq.) was charged along with THF (5 mL, 5V). The reaction mixture was cooled to −20° C. and sodium hydride (60% in mineral oil) was added (0.051 g, 1.1 eq.). Reaction mixture was allowed to stir for 1 h. Methyl Iodide (0.018 g, 1.1) was added into the reaction mixture and stirred at −20° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in water (50 mL) and extracted with EtOAc (50×2). The organic layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford 0.060 g of Crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and Methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 4% Methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.015 g Yield (30%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][N:20]=[N+:21]=[N-:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-4-fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 11.1 mmol) and NaN3 (721 mg, 11.1 mmol) in DMF (50 mL) was stirred at 75° C. under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100/0 to 0/100) to give the desired material. 1H-NMR (400 MHz, DMSO): δ (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m, 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [N:1]([CH:4]([CH3:27])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:18]=[CH:19]3)=[N:14]2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P([C:41]2[CH:46]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:47]>C1COCC1>[CH:24]1([CH2:23][O:22][C:17]2[CH:18]=[CH:19][C:20]3[C:15]([CH:16]=2)=[N:14][N:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH:4]([NH:1][C:46](=[O:47])[CH3:41])[CH3:27])[CH2:8][CH2:9]2)[CH:21]=3)[CH2:26][CH2:25]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1)N=[N+]=[N-]
Reactant: O
Solvent: C1CCOC1
Product: CC(=O)NC(C)CC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-[trans-4-(3-azidobutyl)cyclohexyl]-6-(cyclopropylmethoxy)-2H-indazole (2.45 g), triphenylphosphine (1.75 g), water (30 mL) and THF (30 mL) was stirred at room temperature for 3 days. The organic solvent was evaporated under reduced pressure, and the obtained aqueous solution was acidified with 6N hydrochloric acid (pH=1), and washed twice with diethyl ether. The aqueous solution was basified with potassium carbonate and extracted with a mixed solvent of ethyl acetate/THF (10/1). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in pyridine (30 mL), and acetic anhydride (3.15 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate, ethyl acetate/methanol), and the obtained solid was recrystallized from hexane/ethyl acetate to give the title compound (1.29 g) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].[O:4]=[C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][C:17]([CH:19]=O)=[CH:18][C:6]1=2>N1C=CC=CC=1>[O:4]=[C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][C:17]([CH:19]=[N:2][OH:3])=[CH:18][C:6]1=2
Reactant: NO
Reactant: O=Cc1ccc2oc3ncccc3c(=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c2cc(C=NO)ccc2oc2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
11 g of hydroxylamine hydrochloride is added to a suspension of 30 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde in 600 ml of pyridine, and the mixture is vigorously stirred at 80°C for 1 hour. After cooling, the crystals are filtered off, washed with water, and dried to give crude 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde oxime melting at 254°-256°C with decomposition.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:18][CH2:19][C:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.80 g, 67.1 mmol) in dichloromethane (150 mL) under nitrogen was added triethylamine (11.2 mL, 80.5 mmol. This was then cooled to 0° C. and to this was added dropwise with stirring 2-chloroacetyl chloride (6.53 mL, 80.5 mmol) in dichloromethane (50 mL) over 1 and a half hours. This was then stirred overnight warming to room temperature in the process. The reaction was then quenched by adding 1 N HCl (100 mL). This was then extracted with ethyl acetate and the ethyl acetate layers were dried with solid anhydrous magnesium sulfate powder, filtered and concentrated to give 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one as a brown oil (15.44 g). This was used without purification for the next step.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:9])=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32].Cl>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)=[O:9])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Reactant: CCCn1cncc1CSc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
To (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfenyl}phenylamine di-p-toluoyl-D-tartarate monohydrate (5 g) were added 1N hydrochloric acid (25 ml) and ethyl acetate (15 ml) to effect reverse extraction. To the aqueous layer was added aqueous 25% potassium carbonate solution (25 ml)(pH 9) and the mixture was extracted with 25 ml of ethyl acetate —IPA (4:1) three times. The organic layer was washed with saturated brine (25 ml) and dried with magnesium sulfate. The solvent was distilled off to give (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][CH2:25][CH2:30][CH2:29][OH:31])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:26][CH:27]=1
Reactant: CC(O)Br
Reactant: CNC(C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Product: CC(NCCCO)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(1-methylaminoethyl)phenyl]cyclohexylamine and bromoethanol. Melting point: 118°-120° C.
Reaction SMILES: OC1[CH:10]=[CH:9][CH:8]=[C:7]2C=1[CH2:4][CH2:5][C:6]2=[O:11].[H-].[Na+].[CH3:14]I.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:14][C:5]1([CH3:4])[CH2:17][C:16]2[C:7](=[CH:8][CH:9]=[CH:10][C:20]=2[O:19][CH3:18])[C:6]1=[O:11]
Reactant: C1CCOC1
Reactant: O=C1CCc2c(O)cccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1cccc2c1CC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxy-indanone (25 g) is added portionwise to a stirred suspension of sodium hydride (40.1 g, 60% in mineral oil) and methyl iodide (62.4 g) in anhydrous THF (990 ml) under nitrogen and the mixture is stirred at RT overnight. The reaction mixture is quenched with H2O, washed with diethyl ether and the etheral layer is washed with 10% aq. NaHSO3 and H2O, dried, filtered, and evaporated. The residue is chromatographed (silica gel; eluent=hexane/EtOAC) affording the desired product as a solid.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])=[CH:44][CH:43]=1.[C:57](Cl)(Cl)=[S:58]>>[CH3:56][N:53]1[CH2:52][CH2:51][N:50]([C:48]([C:45]2[CH:44]=[CH:43][C:42]([NH:41][C:57]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([NH2:8])=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[S:58])=[CH:47][CH:46]=2)=[O:49])[CH2:55][CH2:54]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: S=C(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(NC(=S)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)cc2)CC1
Yield: 33 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.9 mg) and (4-amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (39.5 mg) obtained in Step B instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine, and thiophosgene (22.9 μl) instead of triphosgene, in the same manner as Step D in Example 1-D-18, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-231) as a yellow solid (28.1 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(OC)c(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Product: COc1ccc(CNC(=O)CN2CCc3cc(OC)c(OC)cc3C2Cc2cc(OC)ccc2OC)cc1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methoxybenzylamine
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[N:17]1[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([N:35]([CH2:42][CH:43]=[CH2:44])[C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH2:31][CH2:30]2)[CH2:18]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:42]([N:35]([CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C@@H:19]2[C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][N:17]([C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[CH2:10][C:9]([OH:45])=[O:8])[CH2:18]2)[CH2:30][CH2:31]1)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH2:43][CH3:44]
Reactant: C=CCN(c1cccnc1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccccc3)C[C@@H]2c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN(c1cccnc1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 94.8 %

Procedure:
A solution of 2-(R)-(3-(S)-((4-(N-(allyl)-N-(pyrid-3-yl)-amino)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid benzyl ester (37 mg, 0.061 mmol from Step C) in 2 mL MeOH was stirred with 13 mg (0.012 mmol) 10% palladium on carbon under 1 atm of hydrogen using a balloon. After 2 h the mixture was filtered and concentrated to provide 30 mg of the title compound. 1H NMR (500 MHz, CDCl3) δ 0.90-0.93 (t, 3H, J=7.5 Hz), 1.1-3.4 (m, 33H), 6.91-6.93 (d, 1H, J=8 Hz), 7.07-7.1 (m, 1H), 7.2-7.35 (m, 5H), 7.92-7.93 (d, 1H, J=4 Hz), 8.08-8.09 (d, 1H, J=2 Hz). ESI-MS. M/z; (M+H)=519.4 (obs), 519.36 (calc.).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:15]O>C(OCC)C>[Br:2][CH2:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[F:5]
Reactant: O=[N+]([O-])c1cccc(CO)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CBr)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of phosphorus tribromide (4.8 mL) in anhydrous diethylether (100 mL) was added at 0° C. to a solution of (2-fluoro-3-nitrophenyl)methanol (compound 2c-1) (7.52 g, 46.3 mmol) in anhydrous diethylether (130 mL), and the mixture was stirred at 30 minutes at 0° C. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The organic extract was washed in series with saturated sodium hydrogen carbonate solution, water and saturated saline, and dried over magnesium sulfate. The title compound (7.10 g, 70%) was then obtained as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([S:20](=[O:26])(=[O:25])[N:21]=[C:22]([NH2:24])[NH2:23])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[NH2:24][C:22](=[N:21][S:20]([C:14]1[CH:13]=[C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:27])=[O:2])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])(=[O:25])=[O:26])[NH2:23]
Reactant: COC(=O)CC(c1ccccc1)c1ccc(OC)c(S(=O)(=O)N=C(N)N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(CC(=O)O)c2ccccc2)cc1S(=O)(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[3-(diaminomethylene-sulfamoyl)-4-methoxy-phenyl]-3-phenyl-propionic acid methyl ester (400 mg, 1.02 mmol) in a mixture of MeOH and water (30 mL of 1:1 solution) is added LiOH (73 mg, 3.06 mmol). The reaction mixture is stirred at RT overnight. 1 M aqueous HCl is added to neutralise the reaction mixture. The resulting solid is collected by filtration and dried under vacuum to afford the title compound that is used without further purification.