Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([N:33]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38]Cl)[CH3:32]>C(Cl)(Cl)Cl.CO>[CH2:6]([N:13]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:38][CH2:37][CH2:36][CH2:35][C:34]([N:33]([CH2:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[CH2:31][CH3:32])=[O:40])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:14]1=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCc2cc(O)ccc2N1Cc1ccccc1
Reactant: CCN(CC1CCCCO1)C(=O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC1CCCCO1)C(=O)CCCCOc1ccc2c(c1)CCC(=O)N2Cc1ccccc1

Procedure:
Into 50 ml of dimethylformamide were added 1.9 g of 1-benzyl-6-hydroxy-3,4-dihydrocarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. The mixture was heated at 60°-70° C. under stirring, then 3.4 g of N-ethyl-N-(2-tetrahydropyranylmethyl)-5-chloropentanic acid amide was added dropwise gradually thereto. After the addition operation, the reaction mixture was further stirred at the same temperature for 4 hours. Then the solvent was removed by distillation and the residue thus obtained was dissolved in 200 ml of chloroform and the chloroform layer was washed with a diluted hydrochloric acid, 1% NaOH aqueous solution and water in this order, then dried with anhydrous sodium sulfate. The drying agent was removed by filtratoon, and the mother liquor was concentrated, then the residue thus obtained was treated by a silica-gel column chromatography [solvent used was a mixture of chloroform:methanol=20:1 (v/v)]. 0.6 Grams of 1-benzyl-6-{4-[N-(2-tetrahydropyranylmethyl)-N-ethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyril was obtained as in the form of a colorless syrupy substance.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14][CH:15]=C[C:11]=2[N:10]=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43](O)=[O:44])=[C:35]2[CH:34]=[N:33]1.NC1C=NC=CN=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.O>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2[N:37]=[CH:38][N:39]=[C:40]([O:41][CH:42]([CH2:46][O:47][CH:48]([CH3:49])[CH3:50])[C:43]([NH:8][C:12]3[CH:11]=[N:10][CH:15]=[CH:14][N:13]=3)=[O:44])[C:35]=2[CH:34]=[N:33]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cnccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid (Intermediate D2) (300 mg, 0.80 mmol), aminopyrazine (CAS no. 5049-61-6) (84 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (10 mL) and water (10 mL) and the organic phase separated using a phase separation cartridge and evaporated. The residue was purified using reverse phase chromatography, eluting with 25-75% acetonitrile in water to give 2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-isopropoxy-N-pyrazin-2-yl-propanamide (142 mg, 39%). 1H NMR (400 MHz, CDCl3) 1.18-1.22 (6H, m), 3.70-3.78 (1H, m), 4.10 (2H, d), 6.08 (1H, t), 7.40-7.50 (2H, m), 7.51-7.55 (1H, m), 7.62-7.64 (1H, m), 8.24 (1H, s), 8.35 (1H, s), 8.60 (1H, s), 8.80 (1H, s), 9.58 (1H, s); (M+H)+=454; HPLC tR=2.26.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:29][NH2:30].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)=[N:30][NH:29][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methoxy-4-nitrobenzoyl)phenylacetate (1.2 g, 3.2 mmol) and hydrazine hydrate (0.6 mL, 11 mmol) in ethanol (15 mL) as a yellow solid (0.53 g, 1.5 mmol, 47%), mp: 267°-269° C. 1H NMR (CDCl3) 8.60 (s, 1H), 7.86 (d, J=8.5, 1H), 7.49 (d, J=1.5, 1H), 7.13 (dd, J=8.5, 1.5, 1H), 6.85 (s, 1H), 6.59 (s, 1H), 6.06 (s, 2H), 4.01 (s, 3H), 3.48 (s, 2H). Anal. Calcd. for C17H13N3O6 : C, 57.47; H, 3.69; N, 11.83. Found: C, 57.07; H, 3.42; N, 12.01.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:33]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4])(=[O:35])[CH3:34]
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3c(-n4ccnc4)cc(C)nc23)c1Cl
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) in dichloromethane (0.6 ml) were added acetic anhydride (15.6 mg) and pyridine (15.1 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The mixture was concentrated in vacuo, and the residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[3-(N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (53 mg) as colorless amorphous.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]([CH3:30])([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:24]#[N:25]>>[C:24]([C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:19])([F:18])[F:20])[C:6]([C:2]2([F:1])[CH2:3][O:4][CH2:5]2)=[CH:11][N:10]=1)=[O:14])([CH3:30])[CH2:26][CH:27]1[CH2:29][CH2:28]1)#[N:25]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: CC(N)(C#N)CC1CC1
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)CC2CC2)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 2-Amino-3-cyclopropyl-2-methyl-propionitrile (example 66a) as starting materials and isolated (27.5 mg, 26%); MS (ESI, m/z): 416.5 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:77]=[CH:76][CH:75]=[CH:74][C:12]=1[CH2:13][O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:66]C(OC(C)(C)C)=O)[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:66][C@H:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:13][C:12]1[CH:74]=[CH:75][CH:76]=[CH:77][C:11]=1[N:8]=[N+:9]=[N-:10])=[O:16])[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccccc1COC(=O)NCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.45 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,35,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk63) (51 mg, 0.050 mmol) in dichloromethane (0.45 mL), and the mixture was stirred at room temperature for 45 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-((((2-azidobenzyl)oxy)carbonyl)amino)pentanoate (Orn(oAcbz)-pdCpA) (Compound tk64) (42.6 mg, 93%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [BH4-].[Na+].CC(=CC)C.B(F)(F)F.[C:12]1([C:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:21]#[CH:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I:40]I>O1CCCC1.COCCOCCOC>[I:40]/[CH:22]=[CH:21]/[CH:20]([O:19][C:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: II
Reactant: C#CC(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC=C(C)C
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.650 g. (16.91 mole) of sodium borohydride and 3.17 g. (45.2 moles) of 2-methyl-2-butene in 40 ml. of diglyme cooled to -5°C. under an inert atmospere is added over 15 minutes 3.24 g. (22.6 moles) of boron trifluoride ethereate and the resulting mixture is stirred at 0°C. for 2 hours. To this mixture is then added over 5 minutes 8.32 g. (22.6 moles) of 3-triphenylmethoxy-1-octyne (Example 119) in 10 ml. of diglyme, the cooling bath is removed, and the mixture is stirred at ambient temperatures for 1.5 hours. The mixture is cooled to 0°C. and 6.0 g. of finely divided anhydrous trimethylamine oxide is added over 10 minutes. The cooling bath is removed and the mixture is stirred at ambient temperatures for 0.5 hour. The mixture is then poured into 200 ml. of 15% sodium hydroxide solution, a solution of 16 g. (63 moles) of iodine in 20 ml. of tetrahydrofuran is added immediately, and the resulting mixture is stirred for 0.5 hour. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are decolorized with 5% sodium thiosulfate solution, washed with saturated brine, dried (Na2SO4), and evaporated. The residue is dry-columned chromatographed upon alumina using hexane as eluent and the title compound is isolated as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.[NH:45]([C:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[O:51])[CH2:46][C:47](O)=[O:48].Cl>C(OCC)(=O)C.O>[NH:45]([C:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[O:51])[CH2:46][C:47]([NH:1][C@H:2]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OC(C)(C)C
Yield: 117.6 %

Procedure:
His(Trt)-OtBu (15.0 g, 33.1 mmol) and HOBt.H2O (5.13 g, 33.5 mmol) were added to N-palmitoyl-Gly (10.0 g, 31.9 mmol), and the whole was stirred while cooled with ice. Then, WSCD hydrochloride (6.42 g, 33.5 mmol) was added, and the whole was stirred while cooled with ice for 30 minutes and further stirred at room temperature for 18 hours. Water (500 ml) and ethyl acetate (400 ml) were added, and then, the aqueous phase was extracted with ethyl acetate (200 ml). The combined organic phase was successively washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated saline solution, 10% citric acid aqueous solution, and a saturated saline solution, and dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to give 28.1 g (118%) of a target compound as a pale yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:12]=2)/[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Temperature: 47.5 °C
Yield: 99.4 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5 methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (273 mg, 0.7 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (262 mg, 100%) as a yellow solid: EI-HRMS m/e calcd for C17H20N4O4S (M+) 376.1205, found 376.1204.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:14][NH:15][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CN
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
26 g (0.15 mol) of 4-phenylcyclohexanone are stirred with 160 ml of a 6 % methylamine solution in toluene in the presence of 30 g of molecular sieve M 3 Å overnight in a sealed flask. After filtering and concentration by evaporation the residue is dissolved in 200 ml of methanol and at −20° C. 7.8 g sodium borohydride are added batchwise. After it has all been added the mixture is stirred overnight at ambient temperature. After evaporation of the methanol the remainder is taken up in 150 ml of ice water and made strongly acidic with conc. hydrochloric acid. After saturation with common salt the hydrochloride precipitated is suction filtered, the mother liquor is made strongly alkaline with 6N sodium hydroxide solution, extracted with ethyl acetate, dried and evaporated down. The hydrochloride precipitated is suspended in a mixture of water and ethyl acetate and, under cooling, made strongly alkaline with 6N sodium hydroxide solution. The ethyl acetate phase is washed with water and saturated saline solution, dried and evaporated down. Crystallisation of the residue from petroleum ether yields 15.1 g trans-N-methyl-4-phenylcyclohexylamine (colourless crystals). The petroleum ether mother liquor is evaporated down and combined with the evaporation residue from the hydrochloride precipitation. Separation on aluminium oxide (activity stage III, ethyl acetate/petroleum ether=1:1 to 2:1, v:v) yields 2.4 g cis-N-methyl-4-phenylcyclohexylamine,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[OH:37][CH2:38][C:39]1([CH:43](O)[CH3:44])[CH2:42][CH2:41][CH2:40]1>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:22][CH2:23][C:24]3([O:37][CH2:38][C:39]4([CH2:42][CH2:41][CH2:40]4)[CH:43]([CH3:44])[O:27]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(O)C1(CO)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Yield: 91.8 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (23 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (7.6 g), 4-methylbenzenesulfonic acid (0.093 g) and toluene (200 mL) was heated with a Dean-Stark apparatus under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (26 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Sc3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).
Reaction SMILES: O[Li].O.Cl.Cl.[NH2:6][CH:7]([C:48]([O:50]C)=[O:49])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[C:25]([OH:32])=[CH:24][C:23]([OH:33])=[C:22]4[CH:21]=[CH:20][C:19]3=[C:18]([S:34](=[O:47])(=[O:46])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([C:42]([O:44]C)=[O:43])[NH2:41])[CH:17]=1)(=[O:15])=[O:14]>O.CO>[NH2:41][CH:40]([C:42]([OH:44])=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36][NH:35][S:34]([C:18]1[C:19]2[C:30]3=[C:31]4[C:22](=[CH:21][CH:20]=2)[C:23]([OH:33])=[CH:24][C:25]([OH:32])=[C:26]4[CH:27]=[CH:28][C:29]3=[C:16]([S:13](=[O:15])(=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([C:48]([OH:50])=[O:49])[NH2:6])[CH:17]=1)(=[O:46])=[O:47]
Reactant: COC(=O)C(N)CCCCNS(=O)(=O)c1cc(S(=O)(=O)NCCCCC(N)C(=O)OC)c2ccc3c(O)cc(O)c4ccc1c2c43
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: NC(CCCCNS(=O)(=O)c1cc(S(=O)(=O)NCCCCC(N)C(=O)O)c2ccc3c(O)cc(O)c4ccc1c2c43)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
A solution of LiOH.H2O (1.319 g, 31.43 mmol) in water (20 mL) was added to a solution of the dihydrochloride 6 (2.443 g, 3.250 mmol) in methanol (80 mL). The mixture was stirred vigorously at room temperature for 3 h and then concentrated by evaporation. The residue was taken up in 80 ml of water and 4 ml of conc. hydrochloric acid were added. The reaction mixture was concentrated by evaporation once again and then taken up in 100 ml of water, added to a 4 cm×40 cm column packed with acidic Dowex 50WX2-200, washed with 1.5 L of water and then eluted with 1.5 L of 1N ammonia solution. The emerald green solution of 7, which was evaporated under reduced pressure at 50° C., was dried over phosphorus pentoxide overnight to give the dark brown powder 7 (2.0350 g, 96%). The powder was stirred in 20 ml of water at 70° C. for 20 min, cooled and centrifuged. The sediment was stirred in ice-cold water, centrifuged off and dried overnight over phosphorus pentoxide (1.1907 g). Melting point: 210-212° C. (decomposition). 1H NMR (300 MHz, [D6]-DMSO): δ=8.84 (s, 1H), 8.53 (d, J=9.0 Hz, 2H), 8.46 (d, J=9.0 Hz, 2H), 8.15 (br. s, 2H, 2 NH), 7.27 (s, 1H), 3.12 (m, 2H, 2 CHN; overlapping with HOD and NH2), 2.65 (t, J=7.5 Hz, 4H, 2 CH2N), 1.57-1.35 (m, 4H, 2 CH2), 1.30-1.00 (m, 8H, 4 CH2). HRMS (ESI): m/z [M+Na]+ calculated for C28H34N4NaO10S2 673.1614; found 673.1609; m/z [M−H]+ calculated for C28H33N4O10S2 649.1638; found 649.1644.
Reaction SMILES: [CH2:1]([SH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br[CH2:14][CH:15]=[C:16]=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C(OCC)C>[C:20]([O:22][CH3:23])(=[O:21])[CH2:19][CH2:18][CH:17]=[C:16]=[CH:15][CH2:14][S:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCS
Reactant: COC(=O)CCC=C=CCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCSCC=C=CCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A mixture of 376 mg of undecylmercaptan, 438 mg of methyl 7-bromohepta-4,5-dienoate and 0.278 ml of triethyl amine in 2 ml of diethyl ether were stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with hexane and toluene to give 210 mg of methyl 8-thianonadeca-4,5-dienoate having the following NMR spectrum which was run in deutochloroform solution with TMS as the internal standard.