Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.459 g of 6-(3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. Under ice cooling, 0.133 ml of ethyl bromoacetate was added, followed by stirring at room temperature for 4 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.235 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH:6]=1)=[O:4]
Reactant: CN(C)CCCl
Reactant: COC(=O)c1c[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCN(C)C)c2cc(Cl)ccc12
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
To a stirred solution of 80 mg (0.38 mol) of 6-chloro-1H-indole-3-carboxylic acid methyl ester in 5 ml of DMF were added 50 mg of NaH (3 eq, 55H in oil) at RT. After 20 min, 66 mg (0.45 mmol, 1.2 eq.) of (2-chloro-ethyl)-dimethyl-amine hydrochloride were added and stirring was continued overnight at 60° C. Extraction with EtOAc/aq. NH4Cl followed by flash chromatography yielded 45 mg of crude 6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carboxylic acid methyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:31]([NH:33][CH3:34])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:39][CH2:40][N:41]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:42][CH2:43]1)[C:31]([NH:33][CH3:34])=[O:32]
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 11.2 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (97 mg, 0.386 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (113 mg, 0.463 mmol) and 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (112 mg, 0.386 mmol) and DIEA (202 μl, 1.158 mmol). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (21 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.6, 2.0 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.88 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.27 (dd, J=10.6, 3.0 Hz, 1H), 3.40 (s, 2H), 2.92-3.14 (m, 5H), 2.64-2.85 (m, 6H), 2.51-2.64 (m, 3H), 2.45 (dd, J=13.4, 1.5 Hz, 2H). [M+H] calc'd for C23H27ClN6O2S, 487; found, 487.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.[OH:30][C:31]1[C:35]([CH:36]=[O:37])=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:36]([C:35]1[C:31]([O:30][CH2:2][C:3]2[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=4)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=3[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=2)=[N:32][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=1)=[O:37]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.04 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g), anhydrous potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.25 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 195-196° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CCO[C:44]([CH3:46])=O.[CH3:47][C:48]#N.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[C:27]2[CH:32]=[CH:31][C:30]([C:8]3[CH:12]=[CH:11][C:48]([CH2:47][CH2:44][CH3:46])=[CH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(CN(C(=O)[C@@H]2C[C@H]2c2cccc(F)n2)c2ccc(Br)cc2)CCCC1
Reactant: CCOC(C)=O
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1ccc(-c2ccc(N(CC3(NC(=O)OC(C)(C)C)CCCC3)C(=O)[C@@H]3C[C@H]3c3cccc(F)n3)cc2)cc1
Reaction time: 0.33 h

Procedure:
A mixture of [1-({(4-Bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-cyclopentyl]-carbamic acid t-butyl ester (95 mg, 0.18 mmol), arylboronic acid (0.22 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (47 mg, 0.34 mmol) in CH3CN/H2O (3.5/0.5 mL) was macrowaved at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexaneover 25 min) to give the desired products. MS (MH+ 572).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C@@:12]1([OH:28])[C:16]2([CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C@H:15]([CH3:26])[CH2:14][C@@H:13]1[OH:27].CCN(CC)CC>C(Cl)Cl>[OH:28][C@:12]1([CH3:11])[C:16]2([CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C@H:15]([CH3:26])[CH2:14][C:13]1=[O:27]
Reactant: C[C@@H]1C[C@H](O)[C@](C)(O)C12CC(C)(C)CC(C)(C)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H]1CC(=O)[C@](C)(O)C12CC(C)(C)CC(C)(C)C2
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
Under N2 atmosphere with rigorous exclusion of moisture, a solution of dimethyl sulfoxide (340 mg, 4.40 mmol) in CH2Cl2 (1 mL) was injected via syringe at −70° C. within 5 min. into a stirred oxalyl chloride solution in CH2Cl2 (2 M, 1.10 ml, 2.20 mmol) diluted with CH2Cl2 (5 mL). After stirring at this temp. for 5 min., (1R*,2S*,4R*)-1,4,7,7,9,9-hexamethylspiro[4.5]decan-1,2-diol (510 mg, 2.00 mmol) dissolved in CH2Cl2 (1 mL) was injected during 5 min dropwise via syringe. Stirring was continued at −70° C. for 30 min., prior to injection of Et3N (1.01 g, 10.0 mmol). The cooling bath was removed, and the reaction mixture allowed to warm to room temp., prior to pouring into water (50 mL). The organic layer was separated, the aqueous one extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), and concentrated on the rotary evaporator. Purification of the resulting residue by two silica-gel FC (pentane/Et2O, 19:1, Rf=0.17) furnished (1R*,4R*)-1-hydroxy-1,4,7,7,9,9-hexamethylspiro[4.5]decan-2-one (330 mg, 65%).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].[CH2:13]([NH:16][CH3:17])[CH:14]=[CH2:15]>CC(C)=O>[CH2:13]([N:16]([CH3:17])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][OH:6])[CH:14]=[CH2:15]
Reactant: C=CCNC
Reactant: OC/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)C/C=C/CO
Temperature: 25 °C
Reaction time: 40 h

Procedure:
3.58 g of (E)-4-bromo-2-buten-1-ol are dissolved in 100 ml of acetone and treated with 9.84 g of K2CO3 and 3.4 ml of N-allyl-methyl-amine. The suspension is stirred at RT for 40 h., filtered and the crude product obtained after concentration is purified on silica gel with methylene chloride:methanol (gradient 9:1-3:1). 1.52 g of (E)-4-(allyl-methyl-amino)-but-2-en-1-ol are obtained as a colourless liquid, MS: m/e 141 (M).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl>O1CCOCC1>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 100 %

Procedure:
A solution of piperidine-4-carboxylic acid (4.7 g, 36 mmol) in 0.5M aqueous sodium hydroxide (160 ml, 80 mmol) and dioxan (50 ml) was treated with benzyl chloroformate (4.3 ml, 5.13 g, 30 mmol). After 1 hour the mixture was acidified with 5M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, then dried and evaporated affording an oil (7.9 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[N+:14]([O-])=O.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(C)C>C(O)C.[Pd]>[NH2:14][C:4]1[CH:5]=[C:6]([O:9][CH2:10][C@@H:11]([OH:12])[CH2:13][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC[C@@H]2CO2)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)O
Product: COc1ccc(OC[C@@H](O)CN2CCCC2)cc1N
Temperature: 140 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
In a sealed tube were placed (2S)-2-({[4-(methyloxy)-3-nitrophenyl]oxy}methyl)oxirane (1.0 g, 4.4 mmol), pyrrolidine (3.2 g, 44 mmol), and isopropanol (20 mL). The mixture was heated under microwave to 140° C. for 10 min. Removal of the isopropanol afforded the crude product which was placed in ethanol (100 mL) with 10% palladium on carbon (0.5 g). The reation mixture was kept stirring under H2 at 60 psi overnight. Filtration removed the catalyst and concentration afforded (2S)-1-{[3-amino-4-(methyloxy)phenyl]oxy}-3-(1-pyrrolidinyl)-2-propanol (1.1 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (ddd, J=6.4, 3.5, 3.3 Hz, 4H), 2.47-2.50 (m, 1 H), 2.55 (d, J=1.8 Hz, 4 H), 2.64 (dd, J=12.3, 5.7 Hz, 1 H), 3.63-3.71 (m, 4 H), 3.75-3.82 (m, 1 H), 3.83-3.89 (m, 1 H), 4.70 (s, 2 H), 4.88 (s, 1 H), 6.03 (dd, J=8.4, 2.9 Hz, 1 H), 6.24 (d, J=2.9 Hz, 1 H), 6.63 (d, J=8.8 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9]Cl.CC(C)=O.[OH:15][C:16]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]>C(OCC)(=O)C.O>[CH3:7][O:8][CH2:9][O:15][C:16]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:17]=1[C:18]([NH:20][C:21]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]
Reactant: Cc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (0.51 g) and methoxymethyl chloride (0.23 mL) were sequentially added to an acetone (9.0 mL) suspension of tert-butyl 2-(2-hydroxy-5-methylbenzamido)-4-phenylbenzoate (0.60 g), followed by stirring at room temperature for 1 hour and 30 minutes. Potassium carbonate (0.21 g) and methoxymethyl chloride (0.11 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. Potassium carbonate (0.51 g) and methoxymethyl chloride (0.23 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours and then heating to reflux for 20 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.64 g of tert-butyl 2-(2-(methoxymethoxy)-5-methylbenzamido)-4-phenylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243 mg, 1.0 mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg, 1.0 mmol) and purified by HPLC. 1H NMR (CDCl3) δ 10.71 (br s, 1H, NH), 8.63 (dd, 1H, J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz), 7.49 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=9.5 Hz, J=1.8 Hz), 7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H, J=2.6 Hz), 2.29 (s, 3H), 1.29 (s, 9H). MS: m/z 443 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1.C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:48]([C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:55])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.250 g, 0.415 mmol), in tetrahydrofuran (5 mL), were added, nicotinoyl chloride-hydrochloride (0.148 g, 0.83 mmol), triethyl amine (0.210 g, 2.07 mmol, 0.289 mL), and 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification. ES-MS (m/z) 708 [M+1]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](CCC=O)=[CH:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:6])[CH:8]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: [Li]CCCC
Reactant: Cn1cc(CCC=O)c2ccccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCc1cn(C)c2ccccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Methyltriphenylphosphonium bromide (2.06 g, 5.77 mmol) was dried in vacuo for 2 hours then suspended with stirring in tetrahydrofuran (15 ml) under nitrogen. The mixture was cooled to −78° C. and n-butyllithium in tetrahydrofuran (3.75 ml, 5.77 mmol) was added dropwise. After stirring for 2 hours being allowed to warm to room temperature, the mixture was again cooled to −78° C. and 3-(1-methylindol-3-yl)propionaldehyde (90° mg, 4.81 mmol) in tetrahydrofuran (6 ml) was added dropwise. After 2 hours stirring at room temperature, the reaction was quenched by addition of aqueous ammonium chloride. This mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (36 g) chromatography eluting with hexane/ethyl acetate (20:1) to give 3-(3-butenyl)-1-methylindole (539 mg, 60.5%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:20][CH2:21][OH:22])[CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:20][CH2:21][O:22][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:8]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To an ice-cold stirred mixture of (2-hydroxyethyl)-[2-hydroxy-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (5.50 g, 16.8 mmol) and triphenylphosphine (5.17 g, (19.7 mmol) in toluene (80 mL) was added triethylamine (6.15 mL, 4.46 g, 44.2 mmol) followed a solution of di-tert-butylazodicarboxylate (3.10 mL, 19.7 mmol) in toluene (30 mL) dropwise. The reaction mixture was stirred for 18 h at room temperature, washed with water (50 mL), and the aqueous layer was back extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane, the obtained product was triturated with diisopropyl ether and collected. The title compound (3.56 g, 11.5 mmol, 68%) was obtained as a white solid. ESMS m/z 253 (M+H-tBu)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (d, J=8.3 Hz, 2H) 7.57 (d, J=8.3 Hz, 2H) 4.53 (d, J=10.3 Hz, 1H) 4.20 (br. s., 1H) 4.06 (d, J=11.3 Hz, 1H) 3.94 (br. s., 1H) 3.66-3.75 (m, 1H) 3.06 (br. s., 1H) 2.76 (br. s., 1H) 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C@@H:15]([NH3+:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+][C@@H](Cc1ccc(OCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.063 mL, 0.82 mmol) was added to a room temperature solution of [(S)-1-(1H-Benzimidazol-2-yl)-2-(4-benzyloxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.073 g, 0.16 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred at room temperature for 2 hours, and then concentrated in vacuo to give (S)-1-(1H-Benzimidazol-2-yl)-2-(4-benzyloxy-phenyl)-ethylammonium trifluoro-acetate as a red-brown oil. This material was re-suspended in CH2Cl2 (4 mL) and treated with a room temperature solution of PyBOP (0.086 g, 0.16 mmoles), triethylamine (0.080 mL, 0.58 mmol), and (S)-1-(3-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid (0.056 g, 0.16 mmol) in CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature for 16 h. Purification of the product by flash chromatography on silica gel eluting with 10-50% EtOAc/heptane afforded 0.075 g (69%) of the title compound as a colorless powder: ES+ LC/MS m/e 663 (M+H), 100% purity; 1H NMR (CDCl3) ˜1:1 mixture of diastereomers δ10.07 (bd s, 1), 8.07 (s, 1), 7.95 (d, 1, J=7.8 Hz), 7.81 (m, 1), 7.60 (m, 1), 7.24-7.42 (m, 9), 7.10 (d, 2, J=8.6 Hz), 6.88 (d, 2, J=8.6 Hz), 5.25-5.42 (m, 1), 5.04 (s, 2), 4.48 (bd s, 1), 3.32-3.84 (m, 3), 2.88 (m, 1), 1.05-1.77 (m, 6).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>>[CH3:13][C:12]1[C:7]([NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: N[C@H]1CC[C@H](O)CC1
Product: Cc1nc(NCc2ccccn2)nc(N[C@H]2CC[C@H](O)CC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using trans-4-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by crystallization from ethanol to afford the titled compound as a hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.26 (m, 2H), 1.32-1.44 (m, 2H), 1.67 (d, J=11.28 Hz, 2H), 1.80-1.99 (m, 5H), 2.33 (s, 3H), 3.45-3.55 (m, 1H), 3.75-3.83 (m, 1H), 4.72 (s, 2H), 7.33 (bs, 1H), 7.44 (d, J=7.79 Hz, 1H), 7.83 (t, J=7.12 Hz, 1H), 8.53 (d, J=4.30 Hz, 1H); MS (ESI) m/z 328.3 (M+1)+.