Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=[CH:7]1)=[O:5])[CH3:2].CCOC(C)=O>[Pd].CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C=Cc2ccsc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1CCc2ccsc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.00 g), 10% palladium on carbon (2.16 g), AcOEt (30 ml) an, MeOH (10 ml) was stirred at r.t. under hydrogen atmosphere for 4 hours. After removal of insoluble solids, the filtrate was concentrated in vacuo to give 6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (0.96 g) as an oil.
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[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=O)=[O:14]>C(Cl)Cl.FC(F)(F)C(O)=O>[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[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([N:15]1[CH:20]=[CH:19][O:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14]
Reactant: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1COC=CN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester (13.6 g) in methylene chloride/trifluoroacetic acid (10:1/330 mL). Stir at room temperature for 2.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (35% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound (8.52 g, 68%); mp 70°-72° C.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[NH2:10][NH2:11]>CCOCC>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([NH:10][NH:11][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])=[O:5]
Reactant: NN
Reactant: O=C(Cl)CC(F)=C(F)F
Solvent: CCOCC
Product: O=C(CC(F)=C(F)F)NNC(=O)CC(F)=C(F)F
Temperature: -78 °C
Yield: 52.8 %

Procedure:
A solution of 3,4,4-trifluoro-3-butenoyl chloride (2.4 g, 0.0151 mole) in dry ether (20 mL) is treated dropwise with anhydrous hydrazine (0.48 g, 0.15 mole) with stirring at -78° C. The mixture is allowed to reach room temperature and the white precipitate is filtered and dissolved in ethyl acetate. The ethyl acetate solution is washed with 5% sodium bicarbonate and dried. Evaporation of the solvent gave 1.1 g of the desired product as a white solid, a 47% yield. m.p. 191°-193° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[CH3:8][N:9]([CH3:22])[CH:10]=[N:11][C:12]1[S:13][C:14]([CH:20]=O)=[C:15](Cl)[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH3:22][N:9]([CH3:8])[CH:10]=[N:11][C:12]1[S:13][C:14]2[CH:20]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[C:16]=1[C:17]#[N:18]
Reactant: CCOC(=O)CS
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2sc(N=CN(C)C)c(C#N)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
120 parts of ethyl thioglycolate were added to a mixture of 241.5 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)formamidine, 138 parts of potassium carbonate and 1,400 parts of N,N-dimethylformamide. After the slightly exothermic reaction had died down, the reaction mixture was stirred at 50° C. for 2 hours. 1,000 parts of ice, 1,000 parts of water and 150 parts of concentrated hydrochloric acid were then added. The precipitate was filtered off with suction, washed with water and dried. This gave 284 parts (93% of theory) of N,N-dimethyl-N'-(3-cyano-5-ethoxycarbonylthieno[3,2-b]thien-2-yl)formamidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)cc1
Yield: 65 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as a white solid (46 mg, 65%).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C(O)C>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 1,4-cyclohexanedione monoethylene ketal (3.12 g, 20 mmol) in dioxane (25 mL) and ethanol (45 mL) was added NaBH4 (0.38 g, 10 mmol) and the resulting mixture was refluxed for 45 min. The mixture was then cooled to room temperature, acidified to pH 5 with 10% citric acid and extracted with ethyl acetate to afford crude 1-hydroxy-4-cyclohexanone ethylene ketal (2.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: OCC1CCCNC1
Product: N#Cc1c(N)cccc1OCC1CCCNC1

Procedure:
Prepared as in Example 24d from 3-piperidinemethanol and 2-amino-6-fluoro-benzonitrile as a light yellow solid (27%). MS 232 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH3:11][C:3]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][N:6]2[CH:8]=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: C1CCNCC1
Reactant: Cc1cc2nncn2nc1Cl
Solvent: CCO
Product: Cc1cc2nncn2nc1N1CCCCC1

Procedure:
7.8 Grams (0.0462 mole) of the 6-chloro-7-methyl-s-triazolo[4,3-b]pyridazine is mixed with 7.86 grams (0.0924 mole) of piperidine in 50 ml of ethanol. The mixture is heated at reflux temperature for 4 hours. The mixture is concentrated by evaporation and the residue of the reaction mixture is partitioned between aqueous sodium bicarbonate solution and methylene chloride. The methylene chloride layer is separated, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The 7-methyl-6-piperidino-s-triazolo[4,3-b]pyridazine product is obtained as a residue from the evaporation. The product is recrystallized from hexane and found to melt at 78°-79° C. The structure of the product is confirmed by infrared spectroscopy, by nuclear magnetic resonance analysis, and by elemental analysis. (Calculated for C11H15N5 : C, 60.80; H, 6.96; N, 32.24. Found: C, 60.40; H, 6.98; N, 32.17.)
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
6.9 g of BOC-Met-Leu-Gly-OH are dissolved in 70 ml of 90 % strength trifluoracetic acid and left to stand for one hour at 20°C. Thereafter the solution is concentrated, mixed with 150 ml of ether whilst stirring and left to stand overnight at -10°C. The resulting precipitate is filtered off and again stirred with 100 ml of ether, filtered off, twice washed with ether and dried in vacuo over sodium hydroxide. Melting point 134°-135°C; Rf7 = 0.52 (on silica gel).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2)nc1
Yield: 86 %

Procedure:
3-Nitro-6-phenoxypyridine (8.77 g, 40.6 mmol), 10% palladium on carbon (1.20 g) and 1:1 mixed solvent (250 mL) of ethyl acetate with ethanol were mixed and hydrogenation was performed at room temperature under an initial pressure of 196 kPa. After the catalyst was removed by filtration and washed with ethanol, the filtrate was concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 6.50 g (86%) of the title compound as faintly yellow needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55]C.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:6][C:5]=1[OH:55]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.418 g, 0.53 mmol, 1 eq) in CH2Cl2 (9 mL) cooled to 0° C. was added BBr3 (1M in CH2Cl2) (0.800 mL, 0.53 mmol, 1 eq). The reaction was stirred at 0° C. for 40 min, poured over ice and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 to 30% EtOAc:hexane+1% Formic Acid) to afford 2-hydroxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (see next example) and the title compound (0.201 g, 50%) as a white foam. 1H NMR (DMSO-d6) δ 13.60 (bs, 1H); 11.10 (bs, 1H); 8.59 (bt, 1H); 7.96–7.92 (m, 6H); 7.78–7.66 (m, 4H); 7.48 (d, 1H); 7.26–7.10 (m, 5H); 6.26 (d, 1H); 6.21 (dd, 1H); 4.18 (dd, 2H); 3.24 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.27 (m, 8H); IR (film) 3300, 2950, 2800, 1680, 1630, 1590, 1540, 1440, 1320, 1260, 1205, 1160, 1120, 1095, 1080, 990 cm−1; mass spectrum [(−)ESI], m/z 776 (M−H)−; Anal. Calcd. for C43H39F6NO5: C, 67.62; H, 5.15; N, 1.83. Found: C, 67.21; H, 5.11; N, 1.71.
Reaction SMILES: [CH3:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](Cl)=[O:5].CC1CCC([OH:42])C/C/1=C/C=C1\CCCC2(C)C(C(/C=C/C(C(C)C)C)C)CCC\12.C(CN)O>C1C=CC=CC=1>[CH3:1][C:2](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:42])=[O:5]
Reactant: CC1CCC(O)C/C1=C/C=C1\CCCC2(C)C1CCC2C(C)/C=C/C(C)C(C)C
Reactant: CC(=Cc1ccccc1)CC(=O)Cl
Solvent: NCCO
Solvent: c1ccccc1
Product: CC(=Cc1ccccc1)CC(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
194 g of 3-methyl-4-phenyl-3-butenoic acid chloride (1 mole), dissolved into 500 ml benzene, are treated at-10° C with 183 g of monoethanolamine (3 moles). The mixture is stirred at 20° C for 3 hours.
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][O:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[O:15]1[CH2:16][CH2:17][O:18][CH2:19][CH:14]1[C:13]1[C:7]2[S:6][C:5]([NH2:4])=[N:9][C:8]=2[C:10]([O:20][CH3:21])=[CH:11][CH:12]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(C2COCCO2)c2sc(N)nc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
To a stirred solution of 1.10 g (3.39 mmol) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 50 ml dioxane and 50 ml ethylene glycol was added 100 ml of a 5 N aq. sodium hydroxide solution and the mixture was heated at 100° C. for 16 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulfate and concentrated in vacuo. Trituration in methanol afforded 0.66 g (73%) (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:6]1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][C:33]=1[F:41]>ClCCl>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:39](=[O:40])[NH:38][C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([F:41])[CH:34]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@H](c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Temperature: 50 °C

Procedure:
In a 25 mL round-bottom flask, (2S)-1,1,1-trifluoro-3-(2-(6-(trifluoromethyl)pyridin-3-yl)morpholino)propan-2-ol (384 mg, 1.12 mmol) was combined with dichloromethane (12 ml) to give a colorless solution. Triethylamine (113 mg, 155 μl, 1.12 mmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (211 mg, 1.23 mmol) was added. The reaction mixture was warmed at 50° C. overnight. Reaction was complete by LCMS. Two major close-running spots of similar intensity could be seen by TLC (silica 25% EtOAc in hexanes eluent), a front-running spot and a later-running spot. The crude material was purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient). Mixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes gradient). Fractions from both columns that contained pure front-running product were concentrated, dissolved in ether and treated with 1M HCl in ether to form the HCl salt. The salt came out as a sticky semisolid, which turned yellow. The resulting residue was taken up in dichloromethane and free-based by washing with saturated NaHCO3. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes gradient) to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester (146 mg) as a white foam. (M+H)+=516 m/e.
Reaction SMILES: O[C:2]([C:5]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:2]([C:5]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([CH3:4])=[CH2:3]
Reactant: COC(=O)C1(C(C)(C)O)Cc2ccccc2C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)C1(C(=O)OC)Cc2ccccc2C1
Temperature: 100 °C

Procedure:
Into 100 ml of dried pyridine, was dissolved 30.0 g (0.128 mole) of 2-(1-hydroxy-1-methylethyl)-2-methoxycarbonylindane. To the solution, was added dropwise 39.4 g (0.256 mole) of phosphorus oxychloride over a period of 30 minutes at room temperature. The mixture was heated at 100° C. to continue the reaction for further 4 hours. The reaction mixture was cooled to room temperature, poured into a mixture of 10% aqueous hydrochloric acid solution and ice, and extracted with ether. The aqueous layer was extracted twice with ether. The ether layers were combined, washed successively with water, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the intended product as a oily substance.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:63]([CH2:65][C:66](O)=[O:67])#[N:64]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:66](=[O:67])[CH2:65][C:63]#[N:64])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)ccc3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,5-difluoro-phenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (30 mL), HATU (400 mg, 1.05 mmol, 1.5 equiv), triethylamine (220 mg, 2.17 mmol, 3.0 equiv), and 2-cyanoacetic acid (90 mg, 1.06 mmol, 1.5 equiv). The resulting solution was stirred for 10 h at 25° C. and then washed with water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 200 mg (58%) of 3-[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [Mg].C1COCC1.Br[CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[CH2:8]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: BrCC1CC2C=CC1C2
Reactant: CCCCCCCCBr
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCC1CC2C=CC1C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
An oven-dried 3-neck round bottom flask was charged with magnesium turnings (0.809 g, 0.033 mol) and 40 mL of dry THF. 5-Bromomethyl norbornene (6.001 g, 0.032 mol) was added dropwise at room temperature. The mixture was then heated to 50° C. for 18 hours. In a separate flask, 10 mL of dry THF, Li2CuCl4 (5 mL, 0.0005 mol), and 1-bromooctane (6 mL, 0.035 mol) were combined and placed in a −10° C. ice bath. The Grignard reagent, which was transferred via cannula into an addition funnel, was added dropwise to the cooled solution. After the addition was complete, the solution was warmed to room temperature and stirred for 18 hours. The solution was diluted with ether, washed with NH4Cl, brine, and dried over Na2SO4. The solvent was removed and the product was distilled at 76° C. at 0.4 mbar to yield a clear, colorless liquid (4.88 g, 69%). 1H NMR (300 MHz, CDCl3) δ6.12 (1H endo, dd, J=2.74, 5.49); 6.09–5.99 (2H exo, m); 5.93 (1H endo, dd, J=2.74, 5.49); 2.75 (1H, s); 1.98–1.78 (2H, m); 1.40–1.07 (18H, m); 0.89 (3H, t, J=6.05); 0.52–0.45 (1H, m). 13C NMR (75 MHz, CDCl3) δ137.0; 132.6; 49.7; 45.6; 42.7; 38.9; 35.0; 32.6; 32.1; 30.1; 29.9; 29.8; 29.5; 28.9; 22.9; 14.3.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(O)=O.[H][H]>CO>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1N
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (10 g, 46 mmol), HOAc (50 mL) and MeOH (50 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a residue, which was triturated with ether and ethyl acetate. The solid was filtered and dried to give the product as light yellow powder (8.3 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 5.88 (br s, 2H) 6.36 (d, J=16 Hz, 1H) 7.13 (d, J=8 Hz, 1H) 12.32 (br s, 1H). [M+H] calc'd for C8H8FNO3, 186. found 186.
Reaction SMILES: F[C:2](F)(F)[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=O.[NH2:21][CH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]>CO.Cl>[CH:2]1([CH2:3][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([S:15]([NH:21][CH2:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[CH3:29])(=[O:17])=[O:16])=[CH:10][CH:11]=3)[CH2:6]2)[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: CN1CCCC1CCN
Agent: Cl
Solvent: CO
Product: CN1CCC[C@H]1CCNS(=O)(=O)c1ccc2c(c1)CN(CC1CCCCC1)CC2

Procedure:
WO2005/118547 describes a general method of synthesis which is difficult to transpose to the industrial scale for production in large quantities. This method of synthesis entails reacting 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride with (+/−)-2-(2-aminoethyl)-1-methylpyrrolidine, which product is deprotected in methanol and hydrochloric acid. The enantiomers are next separated by chiral chromatography. The resulting N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide undergoes reductive amination with cyclohexanecarboxaldehyde in the presence of a palladium catalyst. 2-(Cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is isolated as the free base and converted to a salt.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18]>>[CH2:20]([O:19][C:17]([C:16]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4][CH:2]([CH3:1])[NH:3][CH:15]=1)=[O:18])[CH2:21][CH3:22]
Reactant: CCCOC(=O)C(=O)CBr
Reactant: CC(N)Cc1c[nH]c2ccccc12
Product: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21

Procedure:
2-Methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester was prepared in the manner described in Example 1A using α-methyl tryptamine and n-propyl 3-bromopyruvate; MS (ESI): 285 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:4]=[CH:5]/[CH3:6]>>[CH3:1][NH:2][CH:5]([CH3:6])[CH2:4][C:3]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C/C=C/C(=O)OCC
Reactant: CN
Product: CCOC(=O)CC(C)NC
Yield: 72.1 %

Procedure:
A solution of 479.2 mL (0.958 mole) methylamine (2M in tetrahydrofuran) was added dropwise to 99.44 gm ethyl crotonate with stirring. After stirring 5 days at room temperature the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was distilled to provide 91.25 gm (72%) of the desired product in 2 fractions.