Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH2:5]([O:12][C:13](=[O:42])[C@@H:14]([NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)(=[O:34])=[O:33])=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:5]([O:12][C:13](=[O:42])[C@@H:14]([NH:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)(=[O:34])=[O:33])=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:1]([CH3:3])[CH3:2])=[CH:18][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1)C1CCCCN1S(=O)(=O)c1cccc(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
Isopropyl iodide (0.62 mL, 6.2 mmol) was added to a mixture of (S)-2-{[1-(3-(fluoro)-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (700 mg, 1.30 mmol) and cesium carbonate (2.4 g, 7.4 mmol) in dry DMF (5 mL). The suspension was stirred at room temperature for 4 h. The reaction mixture was then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed (ethyl acetate/n-heptane) on silica gel to produce 620 mg (82.1%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([N:35]5[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-methanesulfonylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 55 mg of 125. MS (Q1) 528.1 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): Reaction of 0.5 g of 2'-cyanobiphenyl-4-carbaldehyde, 2.5 g of molecular sieve 5 A, 0.815 g of (L)-valine methyl ester hydrochloride and 180 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester after flash chromatography (N3). (TLC: N3) Rf : 0.5.
Reaction SMILES: [ClH:1].[CH2:2]1[CH2:7][CH2:6][C:5]2([CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)[CH2:4][CH2:3]1.[OH2:13]>>[ClH:1].[NH2:11][CH2:12][C:5]1([CH2:8][C:9]([OH:13])=[O:10])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: O
Reactant: O=C1CC2(CCCCC2)CN1
Agent: Cl
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 108 °C
Yield: 60 %

Procedure:
22.3 L of water and 22.3 L of concentrated hydrochloric acid are mixed in a T100 reactor and 6.41 kg gabapentin lactam added while stirring. The clear brown solution formed is subsequently boiled under reflux at 108° C. for 6 hours. The reaction mixture is then left until it has cooled to 28° C. The white precipitate obtained is again dissolved by the addition of a further 40 L of water. For the removal of still undissolved lactam, the reaction mixture is extracted three times with, in each case, 30 L of dichloromethane. The pale yellow aqueous phase is evaporated to dryness in a vacuum evaporator (QVF 100L). At 133 Pa, the temperature finally reached 80° C. The almost dry crystal mass is stirred up with 12.8 L of acetone and sucked off. It is then washed with 2 L of acetone and dried for 4 hours at 60° C. The yield is about 60% of theory.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[S:32]1[CH2:35][CH:34](O)[CH2:33]1.[C:37]([O:41][C:42](=[O:50])[NH:43][CH:44]1[CH2:48][O:47][NH:46][C:45]1=[O:49])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42](=[O:50])[NH:43][C@@H:44]1[CH2:48][O:47][N:46]([CH:34]2[CH2:35][S:32][CH2:33]2)[C:45]1=[O:49])([CH3:40])([CH3:38])[CH3:39]
Reactant: OC1CSC1
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CON(C2CSC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.9 %

Procedure:
A solution of triphenylphosphine (0.79 g) in THF (22 ml) was cooled under argon to −10° C. Diethylazodicarboxylate (DEAD, 1.57 g) was added dropwise then thietan-3-ol (0.4 g) and (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.27 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557). The reaction mixture was stirred at room temperature for 24 hours then the solvent was removed in vacuo. The crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford the title product as a white solid (51 mg). 1H-NMR (CDCl3, 400 MHz): 5.45 (q, 1H), 5.05 (m, 1H), 4.90 (m, 1H), 4.50 (t, 1H), 4.10 (dd, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([F:41])([F:40])[CH:29]([CH3:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([O:30][CH:29]([CH3:39])[C:28]([F:27])([F:40])[F:41])=[CH:32][CH:33]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)F
Yield: 89.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.2 mmol) with (±)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamine (515 mg, 2.3 mmol) in toluene (10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give (±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (530 mg, 90%). GC-MS m/z: 494 (M+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt](=O)=O>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:19]([F:20])([F:21])[F:22])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccccc2)cc1C(F)(F)F
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Platinum dioxide (100 mg, 0.44 mmol) was added to a solution of N-benzoyl 3-(trifluoromethyl)-4-nitroaniline (913 mg, 2.94 mmol) in ethanol (50 ml) at ambient temperature and the reaction stirred for 1.5 hours under an atmosphere of hydrogen. Filtration of the reaction through a pad of celite and solvent evaporation in vacuo, yielded N-benzoyl 3-(trifluoromethyl)-4-aminoaniline (750 mg, 91% yield) as an off-white solid:
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:25][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:8][C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[S:1]1[C:5]([C@H:6]([OH:25])[CH2:7][CH2:8][C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2
Reactant: CC(C)(C)[Si](O[C@H](CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1CC[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-((R)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)propyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (1 molar equivalent) is dissolved in THF (0.3 M) under a nitrogen atmosphere. A solution consisting of TBAF in THF (1 M, 1.2 molar equivalents) is added and the reaction mixture is stirred at room temperature. Upon completion, as judged by TLC, water is added and most of the THF is removed under reduced pressure. The remaining aqueous solution is extracted with ethyl acetate and is washed with water and brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (+0.4% acetic acid) to afford the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:19]3[O:20][C:21]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][C:23](=[O:25])[CH:24]=3)[S:8][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+:33]>CO>[Na+:33].[N:26]1([C:21]2[O:20][C:19]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:14]=3[S:15][C:16]3[CH:17]=[CH:18][C:5]([C:3]([O-:4])=[O:2])=[CH:6][C:7]=3[S:8]4)=[CH:24][C:23](=[O:25])[CH:22]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 80 °C

Procedure:
6-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-thianthrene-2-carboxylic acid methyl ester (1.1 g, 2.43 mmol) and NaOH Pellets (97 mg, 2.43 mmol) were dissolved in methanol (40 ml). The brown suspension was heated to 80° C. under N2 for 24 hours. The solvent was removed in vacuo and the residue was triturated with diethyl ether. The product was collected by filtration as a fine dark brown powder (1.11 g, 99%). m/z (LC-MS, ESP), RT=3.90 min, (M++1)=438
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[OH:12][C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:24]=O>O.CO>[OH:12][C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:24]=[N:2][NH:3][C:4]([NH2:6])=[O:5]
Reactant: O=Cc1c(O)c(O)cc2ccccc12
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NN=Cc1c(O)c(O)cc2ccccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
86.0 g of semicarbazide hydrochloride dissolved in 500 ml of water and 103 g of sodium acetate (CH3COONa.3H2O) were placed in a 2.5 l sulfonation flask equipped with stirrer, thermometer and dropping funnel. At an internal temperature of 40°-50° C., there was added dropwise a solution of 138.4 g of 2,3-dihydroxy-naphthaldehyde in 1000 ml of methanol. The mixture was stirred at 40°-50° C. for 1 hour and then, after adding 2 l of water, cooled to 10° C. and suction filtered. The material on the suction filter was back-washed thoroughly with water and dried at 60° C. in vacuo. Recrystallization from glacial acetic acid gave 131.9 g (73.1% of theory) of 2,3-dihydroxy-naphthaldehyde semicarbazone of melting point 210°-215° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:9]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[CH3:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (965 mg, 2.86 mmol) in dichloromethane (10 mL) was cooled to 0° C. 4-(dimethylamino)pyridine (35 mg, 0.29 mmol), triethylamine (0.60 mL, 4.29 mmol), and acetic acid anhydride (0.32 mL, 3.43 mmol) were added. The reaction mixture was stirred for 5 hours, while it was warming slowly to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined and washed with saturated sodium hydrogen carbonate solution. They were dried over magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/dichloromethane (1:3 to 1:1) to give 890 mg of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Br:3])[N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Br)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
86.0 g (0.3 mol) of phosphorus oxybromide was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 200 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 200 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 11.1 g (0.052 mol) of a pale yellow crystal of 2-amino-6-bromopurine (yield 52%). Its properties are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH2:26]>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH3:19])[N:7]=[CH:6][N:5]=2)=[O:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CC1CCCCC1N
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCC2C)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and 2-methylcyclohexylamine (Aldrich), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([C:4]3[C:20]4[N:19]([C:18]([CH3:17])=[N:22][CH:21]=4)[CH2:2][CH2:3][CH:1]=3)=[CH:11][CH:10]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ncc[nH]1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)C1CC1
Product: Cc1ncc2n1CCC=C2c1ccc(-n2ccnc2)cc1

Procedure:
Combine 100 g (0.47 mol) of cyclopropyl-[4-(1H-imidazol-1-yl)phenyl]methanone with 300 g (3.7 mol) of 2-methylimidazole and heat to 175° C. under argon for 14 hr. Crystallization from acetonitrile provides the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=C(CCl)c1cccc(F)c1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Reaction time: 17 h

Procedure:
A mixture of 5-nitroindoline (I, 12.012 g) in pyridine (100ml) and acetic anhydride (50 ml) is stirred for 17 hr under argon. The mixture is then concentrated under reduced pressure to give the title compound, mp 175°-177°; NMR (CDCl3, 300 MHz) 8.28, 8.10, 8.01, 4.23, 3.31 and 2.28 δ; CMR (CDCl3, 75.47 MHz) 23.95, 27.01, 49.11, 115.73, 119.93, 124.27, 132.4, 143.4 and 169.8 δ; IR (CHCl3) 1680, 1600, 1480, 1470, 1390, 1340 and 1320 cm-1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([CH2:11][NH:12][C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:6]1)(=[O:4])=[O:3].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+]>C(Cl)Cl>[CH3:39][N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C@@H:7]4[O:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]4)[C:22]4[C:17](=[N:18][CH:19]=[CH:20][N:21]=4)[CH:16]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cc4nccnc4c(NC[C@H]4CN(S(C)(=O)=O)CCO4)n3)cc2)CC1

Procedure:
A solution of (S)—N-((4-(methylsulfonyl)morpholin-2-yl)methyl)-7-(4-(piperazin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-amine (60 mg, 0.12 mmol), Formalin (48 mg, 0.48 mmol) and NaBH(AcO)3 in 5 mL of DCM, was stirred at room temperature for 2 hours. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:10˜10:1) to give 46 mg of title compound. MS (m/z)=498 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(Cl)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,4-dichlorobenzene and isolated as white solid (5.3 mg, 29%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>[OH-].[Na+].[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccc(O)c(C(=O)O)c2)ccc1O
Temperature: 120 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-hydroxy 5-chlorobenzoic acid (3.4 g, 20 mmol) was dissolved in 45 cm3 of a sodium hydroxide solution (10% w/v) and palladium on charcoal (10%, 0.5 g) was added. The mixture was placed in a glass liner in an autoclave which was flushed thoroughly with carbon monoxide, then pressurised with carbon monoxide to 2 MNm-2 and heated to 120° C. with stirring for three hours. The mixture was then allowed to cool, the catalyst removed by filtration, and the product precipitated from the aqueous solution by acidification to pH1 with 1M hydrochloric acid. The coupled product (4,4'-dihydroxybiphenyl 3,3'-dicarboxylic acid) was obtained in 80% yield.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])[C@@H:8]([CH3:10])[OH:9]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:9][C@H:8]([CH3:10])[C:7]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: C1=COCCC1
Reactant: CC(C)COC(=O)[C@@H](C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
21.8 g (0.26 mole) of 3,4-dihydro-2H-pyran was dropwise added at room temperature to a mixture of 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 4 hours. After the reaction, 100 ml of ethyl acetate was added, followed by washing with 70 ml of a saturated aqueous sodium hydrogen carbonate solution, 70 ml of water and 70 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 49.0 g (yield: 92.1%) of an oily title compound (diastereomixture).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)cc(F)c1
Product: CC1Cn2c(cc(OCc3cc(F)cc(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.