Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:10].[CH3:14][C:15](=[CH2:17])[CH3:16]>C(O)(=O)C>[C:15]([NH:8][C:7](=[O:10])[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])([CH3:16])([CH3:14])[CH3:17]
Reactant: C=C(C)C
Reactant: CC(C)(C)C(=O)C#N
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Temperature: 25 °C
Yield: 87 %

Procedure:
There were present in a stirrer apparatus protected against moisture 111 grams (1.0 mole) of pivaloyl cyanide, 150 grams (1.5 moles) of concentrated sulfuric acid and 150 ml of glacial acetic acid and there were led in during one hour under stirring at 0°-5° C.112 grams (2.0 moles) of isobutylene. Then the mixture was warmed up to room temperature and stirred further for 4 hours. Then the mixture was poured on 500 grams of ice and after thorough stirring the precipitated amide was filtered off with suction. After the drying in the vacuum drying cabinet, there were isolated 161 grams of analytically pure trimethyl pyruvic acid-N-t-butylamide which corresponds to a yield of 87% based on the acyl cyanide employed. The amide has a melting point of 65° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:7][C:8]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:11])[CH3:6])=[N+]=[N-]>C(O)C.ClCCl.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:7][C:8]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:11])[CH3:6]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN=[N+]=[N-])cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of (S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (505 mg) in a mixture of ethanol (5 mL) and dichloromethane (3 mL) was added 10% palladium on activated carbon (60 mg), and the mixture was stirred under hydrogen atmosphere (1 atm) for 3 hours at ambient temperature. The resulting mixture was filtered through celite and washed with ethanol. The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with 10% methanol in chloroform to give (S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (393 mg) as a solid substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:17])[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2[C:4]([N:3]=1)=[N:17][C:18](=[O:19])[N:16]=2
Reactant: Nc1nc(N)c(N)c(OCC2CCCCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(OCC2CCCCC2)c2c(n1)=NC(=O)N=2
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of 2,5,6-triamino-4-cyclohexylmethyloxypyrimidine (1.0 g, 4.24 mmol) and 1,1′-carbonyldiimidazole (0.69 g, 4.24 mmol) in anhydrous DMF (5 ml) was stirred under nitrogen at ambient temperature for 48 h. Addition of water (100 ml) afforded a white solid which was collected by filtration, redissolved in 2 M sodium hydroxide solution (200 ml), and filtered. The filtrate was neutralised with glacial acetic acid and allowed to stand at 4° C. for 2 h, when the precipitate which deposited was collected and washed thoroughly with water. Recrystallisation from aqueous ethanol yielded the required product (0.65 g, 58%), m.p. 297° C.; (Found: C. 54.66; H, 6.47;. N, 26.63% C12 H17 N5O2 requires C, 54.75; H, 6.46; N, 26.62%); δH (200 MHz, d6-DMSO) 1.04-1.39 (δH, m, C6H11), 1.76-1.90 (6H, m, C6H11), 4.17 (2H, OCH2, J=6.53 Hz), 6.15 (2H. br s, NH2), 10.49 (1H, br s, NH), 1 1.09 (1H, br s, NH); m/z (+EI) 263 (M+, 75%), 167 (MH+—C7H13, 100), 81 (6), 69 (7).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3].C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(Br)nc1Br
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Temperature: 115 °C
Yield: 54.1 %

Procedure:
To a solution of 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole (5.00 g, 14.3 mmol) in 1,4-dioxane (133 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (5.14 g, 17.2 mmol), lithium chloride (1.82 g, 43.0 mmol), copper (I) iodide (0.818 g, 4.30 mmol) and tetrakis (triphenylphosphine)palladium(0) (1.24 g, 1.07 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 4 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (3.13 g, 54%). LCMS: (FA) ES+, 406. 1H NMR (400 MHz, d6-DMSO) δ: 10.77 (s, 1H), 8.66-8.61 (m, 1H), 8.49-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.49-7.45 (m, 1H), 5.98-5.87 (m, 1H), 5.19-5.12 (m, 1H), 4.95-4.88 (m, 1H), 4.70-4.64 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])[C@@H:3]([CH3:12])[O:4]CC1C=CC=CC=1.CCCCCC>CCOC(C)=O.[Pd]>[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:2]([C:13]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])[C@@H:3]([CH3:12])[OH:4]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCCC1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Pd/C (3.3 g) was added to a stirring solution of Boc-Thr(Bzl)-OcHex (11 g, 30 mmol) in AcOEt (80 mL), and the reaction mixture was vigorously stirred under a hydrogen atmosphere for overnight. The catalyst was filtered off through Celite and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, at first with AcOE:hexane 1:4 and then the desired product was washed out by AcOE:hexane 1:1 to give pure Boc-Thr-OcHex (8.6 g, 28 mmol, 94%). 1H NMR (CDCl3 400 MHz) b 5.26 (br. d, 1H), 4.89-4.82 (m, 1H), 4.30-4.20 (m, 2H), 1.94 (d, J=5.6 Hz, 1H), 1.86-1.83 (m, 2H), 1.74-1.70 (m, 2H), 1.57-1.48 (m, 3H), 1.46 (s, 9H), 1.44-1.30 (m, 3H), 1.25 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
To a solution of L-leucinol (1.00 g, 8.53 mmol) in methylene chloride (30 ml) were added chloroformic acid benzyl ester (1.46 ml, 10.2 mmol) and triethylamine (1.43 ml, 10.2 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed With saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamic acid benzyl ester (2.31 g, yield 100%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:11].[CH3:12][Li].Cl>CCOCC>[OH:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](=[O:7])[CH3:12]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1cccc(C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a colorless solution of 3-methyl-salicylic acid (1 g, 6.57 mmol) in Et2O (50 mL) under argon and cooled down to 0° C. was added dropwise methyllithium 1.6M in Et2O (12.32 mL, 19.72 mmol) over 20 min. The resulting mixture was stirred at this temperature for 30 min then allowed to warm up and stir overnight at RT. The reaction mixture was slowly poured into a stirred mixture of 100 g of ice and HCl 4N (50 mL) and extracted twice with EtOAc. The combined organic layers were washed with 10% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product (920 mg, 5.94 mmol, 90% yield) as a pale yellow oil. tR: 0.91 min (LC-MS 2); ESI-MS: 481/483 [M+H]+, ESI-MS: 479/501 [M−H]− (LC-MS 2); Rf=0.55 (hexane/EtOAc 3:1).
Reaction SMILES: FC1(F)[CH2:7][CH2:6][N:5]([CH:8]([C:11]2[CH:16]=CC(C(F)(F)F)=C[CH:12]=2)[CH2:9][NH2:10])[CH2:4][CH2:3]1.[CH:22]1([C:25]2[N:30]=CC(C=O)=C[N:26]=2)[CH2:24][CH2:23]1.N1CC[O:36]CC1>>[CH:22]1([C:25]2[N:30]=[CH:12][C:11]([CH:8]([N:5]3[CH2:4][CH2:3][O:36][CH2:7][CH2:6]3)[CH2:9][NH2:10])=[CH:16][N:26]=2)[CH2:24][CH2:23]1
Reactant: O=Cc1cnc(C2CC2)nc1
Reactant: NCC(c1ccc(C(F)(F)F)cc1)N1CCC(F)(F)CC1
Reactant: C1COCCN1
Product: NCC(c1cnc(C2CC2)nc1)N1CCOCC1

Procedure:
This compound was prepared using a method analogous to that of 2-(4,4-difluoropiperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)-ethanamine (A.2.18), 2-cyclopropylpyrimidine-5-carbaldehyde replacing 4-(trifluoromethyl)benzaldehyde and morpholine replacing 4,4-difluoropiperidine HCl.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:11]([N+:20]([O-])=O)=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH3:19])=[CH:13]3)[CH:5]=[CH:4][C:3]=1[CH2:23][C:24]([OH:26])=[O:25].O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH3:34]O>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[NH2:20][C:11]1[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[C:2]([CH3:1])[C:7]=2[CH3:8])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:19])[NH:15]2
Reactant: CO
Reactant: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(C)c1C
Temperature: 60 °C

Procedure:
Under an N2 atmosphere, 2-(2,3-dimethyl-4-(2-methyl-4-nitro-1H-indol-5-yloxy)phenyl)acetic acid (0.335 g, 0.946 mmol) was suspended in methanol and tin chloride dihydrate (1.71 g, 7.57 mmol) was added. The reaction was heated to 60° C. for 16 h. The reaction was diluted with ethyl acetate and 10% NaHCO3 (aq). The layers were separated and the organic layer was washed with water (3×), dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 20% to 80% ethyl acetate in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 339.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.Br.Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[OH:31])[N:24]=[C:23]2[CH2:32][CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[CH2:37][CH2:38]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: Oc1ncnc2nc(CC3CCNCC3)n(Cc3ccc(F)cc3)c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCN2CCC(Cc3nc4ncnc(O)c4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 1.9 parts of 1-(2-chloroethyl)-4-methoxybenzene, 5 parts of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-ol dihydrobromide, 4 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. After cooling, the reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetontrile. The product was filtered off and dried, yielding 2.2 parts (46%) of 7-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-7H-purin-6-ol; mp. 122.2° C. (compound 62).
Reaction SMILES: [OH:1][CH:2]([CH2:27]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16].[BrH:29].O.C(=O)(O)[O-].[Na+].[C:36]([OH:39])(=O)[CH3:37]>>[C:36]([O:1][CH:2]([CH2:27][Br:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])(=[O:39])[CH3:37]
Reactant: CC(=O)O
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCCC(O)CO)c(=O)n2C
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(12,13-Dihydroxy-tridecyl)-3,7-dimethylxanthine (1.15 g, 2.92 mmol) was stirred with hydrogen bromide (2.84 mL of a 30% solution in acetic acid, 8.76 mmol) for 2 hours. The mixture was then added over 10 minutes to water (20 mL), ice (15 g) and sodium bicarbonate (5 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (2×50 mL), and the combined organic phases were dried using magnesium sulfate and the solvent evaporated to obtain a residue of 1-(12-acetoxy-13-bromotridecyl)-3,7-dimethylxanthine. Without further purification, this crude residue was taken up in methanol (5 mL) and treated with a solution of sodium methoxide (prepared from sodium, 0.069 g, 3.00 mmol, and 5 mL methanol). After 40 minutes, the reaction mitxure was added to water (15 mL) and extracted with dichloromethane (3×30 mL). The organic portions were combined, dried and the solvent evaporated to yield 1.00 g (91% yield) 1-(12,13-Oxidotridecyl)-3,7-dimethylxanthine (inventive compound no. 2562) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: CCCCO
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 192 %

Procedure:
Heat a solution of 5-fluoro-2-nitro-benzaldehyde (10 g, 59.17 mmol), butanol (20 mL, 219 mmol) and p-toluenesulfonic acid (600 mg, 3.15 mmol) in toluene (200 mL) at reflux for 2 hours in a flask equipped with a Dean-Stark trap. Cool the reaction mixture to room temperature, dilute with ethyl acetate (400 mL), and wash sequentially with saturated aqueous sodium bicarbonate (300 mL×3) and saturated aqueous sodium chloride (300 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a pale yellow oil (17 g, 96%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(Cl)Cl>[C:25]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under N2, of 24.6 g of 1-(2-aminophenyl)indoline hydrochloride in 225 ml of dry CH2Cl2 is treated with 20.2 g of triethylamine over 10 minutes. The mixture is cooled to 0°-5° C., and kept at that temperature while a solution of 14.1 g of benzoyl chloride and 25 ml of CH2Cl2 is added dropwise over 1.0 hour. After stirring at room temperature overnight, H2O was added and the layers are separated. The organic phase is washed further with H2O, 3 N--HCl, 3 N--NaOH, again with H2O, and dried. The solvent is removed to leave an oil which crystallizes on standing to yield 1-(2-benzamidophenyl)indoline, m.p. 73°-76° C.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:24][C:25]1([C:28]2[CH:29]=[C:30]([NH:40][C:41]([NH:43][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]([O:54][CH:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)=[N:46][CH:45]=3)=[O:42])[N:31]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:32]=2)[CH2:27][CH2:26]1.[CH3:61][C:62]1([C:65](O)=[O:66])[CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:61][C:62]1([C:65]([N:58]2[CH2:59][CH2:60][CH:55]([O:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:44]([NH:43][C:41]([NH:40][C:30]4[N:31]([C:33]5[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=5)[N:32]=[C:28]([C:25]5([CH3:24])[CH2:27][CH2:26]5)[CH:29]=4)=[O:42])=[CH:45][N:46]=3)[CH2:56][CH2:57]2)=[O:66])[CH2:64][CH2:63]1
Reactant: CC1(C(=O)O)CC1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place EDCI (0.147 g, 0.77 mmol), HOBt (0.10 g, 0.77 mmol), 1-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[1-(piperidin-4-yloxy)-isoquinolin-4-yl]-urea dihydrochloride (Preparation 3, 0.16 g, 0.64 mmol) and 1-methyl-1-cyclopropyl carboxylic acid (1.1 eq) in a flask under N2. Add dichloromethane (5 mL) follow by DIPEA (0.22 mL, 1.28 mmol) and stir at room temperature overnight. Evaporate solvent to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 50-100% to give 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a free base. ES+ (m/z) 579.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])O.[K+].IC>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([O:14][CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccnc(OCc2ccccc2)c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
To a suspension of 2-(benzyloxy)isonicotinic acid (12.6 g) and potassium hydrogencarbonate (8.3 g) in N,N-dimethylformamide (180 mL) was added dropwise iodomethane (4.8 mL) under ice-cooling, and then stirred at room temperature for 7 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride (×3), and then dried over anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (13.07 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[NH2:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(F)cc1

Procedure:
A mixture of 29.7 g. (0.231 mole) of 4-fluorothiophenol, 41 g. (0.238 mole) of 2-chloro-5-nitroaniline and 14.9 g. (0.266 mole) of potassium hydroxide in 500 ml. of 95 percent aqueous ethanol is heated to its reflux temperature and maintained at reflux for one hour, then cooled with an ice bath. Some crude product is isolated as a solid by filtration, then the filtrate is diluted with water and extracted with four 300 ml. portions of chloroform. The combined extracts are washed with four 300 ml. portions of water and then with saturated sodium chloride solution and dried. Evaporation under vacuum provides a residue which is combined with the previously isolated crude solid product, 2-(4-fluorophenylthio)-5-nitroaniline. The solid is dissolved in 500 ml. of chloroform, then the solution is saturated with hydrogen chloride gas. The white precipitate which forms is separated by filtration, washed with chloroform and diethyl ether and dried to provide 2-(4-fluorophenylthio)-5-nitroaniline hydrochloride.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.CS(C)=O.[C-:25]#[N:26].[Na+].Cl[O-].[Na+]>O>[C:25]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)#[N:26]
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [O-]Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(CCCC1CCCCC1)c1ccc(CCC#N)cc1

Procedure:
9 Grams of the 4-[p-(2-chloroethyl)phenyl]pentylcyclohexane, 100 ml of dimethyl sulfoxide ((CH3)2SO) and 23 g of sodium cyanide (NaCN) were stirred together at 140° to 150° C. for 2 hours. After the resulting mixture was cooled, a 10% aqueous sodium hypochlorite (NaClO) solution was added. Further, water was added thereto, and the precipitate was recrystallized from ligroin to obtain 4-[p-(2-cyanoethyl)phenyl]pentylcyclohexane. The melting point of this compound was 44° to 46° C.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:16][C:15]([Br:25])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:25][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(Cl)ccc12
Temperature: 80 °C
Yield: 85.9 %

Procedure:
1.2-Dichloroethane (4.4 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-chlorophenyl)isonicotinate (2.42 g, 6.58 mmol), rhodium octanoate dimer (0.41 g, 0.53 mmol) and crushed 4A° molecular sieves (2.5 gm) and heated at 80° C. for 24 hr. The reaction was diluted with THF and filtered. The collected solid was washed with multiple portions of hot THF to extract remaining product. The solvent was removed from the combined filtrates and the residue was suspended in MeOH and the product was collected by filtration to leave methyl 2-bromo-7-chloro-5H-pyrido[3,2-b]indole-4-carboxylate (1.92 g, 5.65 mmol, 86% yield) as a gray solid. MS (ESI) m/z 340.99 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89 (1H, s), 8.19 (1H, d, J=8.24 Hz), 7.92 (1H, s), 7.76 (1H, d, J=1.53 Hz), 7.35 (1H, dd, J=8.55, 1.83 Hz), 4.04 (3H, s).