Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][NH:29][CH3:30]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:29]([CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[CH3:30])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CNCCN(C)C
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N(C)CCN(C)C)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 66 μL of N,N,N′-trimethylethylenediamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylnicotinamide. MS (Q1) 424.0 (M)+.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)C(=O)C.[OH-].[K+]>C(O)C>[CH3:1][NH:2][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1
Reactant: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc(-c2ccc3nnc(C)n3n2)c1
Yield: 101.5 %

Procedure:
A mixture of 13.5 g of N-methyl-N-[3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]acetamide and 10 g of potassium hydroxide in 500 ml of ethanol was heated to reflux for 12 hours. The solution was concentrated in vacuo and the residue partitioned between 200 ml of brine and 300 ml of dichloromethane. The aqueous layer was extracted with 150 ml portions of dichloromethane. The combined organic layer and extracts were dried, concentrated in vacuo and the residue recrystalized from dichloromethane-hexane, to give 11.66 g of yellow crystals, mp 223°-226° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[CH2:35]([O:34][C:32](=[O:33])[C:31]([CH3:38])([CH3:37])[CH2:30][NH:29][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH3:36]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carboxylic acid butyl ester (19 mg, 0.05 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (29 mg, 0.20 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 18 mg. MS: (−) m/z 446.33 (M−1).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1>C1COCC1.[NH4+]>[Br:8][C:9]1[C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: COc1cc(Cl)c(Br)cn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OCC2CC2)c(Br)cn1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of cyclopropylmethanol (446 mg, 6.18 mmol) in THF (10 mL) was added NaH (247 mg, 6.18 mmol, 60% in mineral oil) in one portion at 0° C. The reaction mixture was warmed up to 20° C. over a period of 30 mins and stirred at 20° C. for 10 mins. Then 5-bromo-4-chloro-2-methoxypyridine (550 mg, 2.47 mmol) was added in one portion and the mixture was stirred at 70° C. for 4 hours. The mixture was diluted with saturated ammonium aqueous solution (50 mL) and extracted by EtOAc (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (PE: EA=20:1 to 10:1) to afford the title compound (450 mg, 70.6%) as colorless oil. 1H NMR: (CDCl3, 400 MHz) δ: 8.11 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.89-3.88 (m, 2H), 1.39-1.27 (m, 1H), 0.70-0.67 (m, 2H), 0.46-0.43 (m, 2H). LCMS (M+H)+=258.0 (M+1)+; 260.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:57][C:58]1[CH:63]=[CH:62][C:61]([S:64]([O:67][CH2:68][CH2:69]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:66])=[O:65])=[CH:60][CH:59]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:69][CH2:68][O:67][S:64]([C:61]3[CH:62]=[CH:63][C:58]([CH3:57])=[CH:59][CH:60]=3)(=[O:66])=[O:65])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(CCc3cncc([C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]4CCCN(C(=O)CCC5CCN(C(=O)OC(C)(C)C)CC5)C4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (67 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (9.7 mL). Cesium carbonate (79 mg, 0.24 mmol) and ethane-1,2-diyl bis(4-methylbenzenesulfonate) (54 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 4 hours, quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20% to 100% followed by dioxane in ethyl acetate 0 to 60%) to yield 64 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32](O)=[O:33])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:33])[CH2:27]2
Reactant: O=C(O)CCC1C2CC3CC(C2)CC1C3
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 44.1 μl was added to a methylene chloride of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 50.0 mg and stirred at 0° C. for 30 min. 3-(2-adamantyl) propionic acid 60.4 mg and WSC 65.7 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 13 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-[3-(2-adamantyl)propionyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 5 ml solution of lithium aluminum hydride 12.0 mg and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of, silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[NH:29][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:24][O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (550 mg, 2.7 mmol), (S)-3-benzyloxy-2-tertbutoxycarbonylaminopropionic acid (880 mg, 3.0 mmol), HOAt (410 mg, 3.0 mmol), 4-methylmorpholine (0.65 mL, 5.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (580 mg, 3.0 mmol) in DCM (13 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-2-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a red oil (1.1 g, 83%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: C#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy-benzene-sulfonyl)-piperdine-4-carboxylic acid ethyl ester (5 g, 9.59 mmol) dissolved in THF:methanol (150:50 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.4 g (72%); brown low melting solid; MS: 491.9 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1csc(N)c1C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1scc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-methyl-thiophene-3-carboxylic acid amide (5 g, 32 mmol) in DCM (100 mL) is cooled to 0° C. Dry pyridine (3.6 mL, 45 mmol) is added, followed by acetylchloride (11 mL, 156 mmol) which is added dropwise to the solution. The resulting mixture is stirred at room temperature overnight, then diluted with DCM and washed with aqueous NaHCO3. The organic phase is dried over MgSO4, filtered and concentrated. The obtained residue is triturated in di-isopropylether, filtered, and the cake is dried to afford the desired product.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:6]=[CH:5][C:4]1=2)#[N:2]>P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1>[C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:8][C:9]=2[C:10]([CH3:13])([CH3:14])[CH2:11][CH:12]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C#N)O[Si](C)(C)C)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C#N)cc1
Temperature: 115 °C

Procedure:
To 215 mg (0.48 mmol) of ethyl 4-[(5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 107) was added 0.5 ml of pyridine and 3 drops of phosphorous oxychloride. The resulting dark mixture was gently refluxed at 115° C. for 30 minutes, cooled to room temperature and poured into crushed ice. The mixture was extracted with Et2O and the combined organic layers were washed with water, dilute HCl and water. The organic phase was concentrated in vacuo to a gummy residue which was purified by flash chromatography (silica, 20% EtOAc-hexane) to yield the title compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH:17]=1.O.[OH-].[Na+]>CN1CCCC1=O>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([NH:25][C:5]3[CH:6]=[CH:7][C:8]([N:10]4[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1Nc1cccc(-c2cccnc2)c1
Temperature: 127.5 °C

Procedure:
A mixture of 1a (0.5g, 2.4mmol) and 2a (0.41g, 2.4mmol) in N-methyl-2-pyrrolidone (2.5ml) is heated to 120-135° C. for 2 days. After cooling water and diluted sodium hydroxide is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate, and the solvent is evaporated to leave crude 3a. This crude product is purified by column-chromatography on silica gel using dichloromethane and subsequently a mixture of dichloromethane and methanol (9:1) as the eluents to yield pure 3a (0.61g, 71%) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH2:18]([O:25][CH2:26][CH:27]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=CCOCc1ccccc1
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(CCOCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of phenylmethyl (2S)-2-methyl-1-piperazinecarboxylate (commercially available) (1 g, 4.3 mmol) and benzyloxyacetaldehyde (0.9 mL, 6.4 mmol) in DCM (50 mL) was stirred for 30 minutes, and then NaBH(OAc)3 (1.36 g, 6.4 mmol) was added. The reaction was stirred overnight before being quenched with 1 M NaOH. The phases were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over sodium sulfate and concentrated to a crude residue, which was purified by silica gel chromatography (5-95% EtOAc in hexane) yielding phenylmethyl (2S)-2-methyl-4-{2-[(phenylmethyl)oxy]ethyl}-1-piperazinecarboxylate (0.93 g, 58%). LCMS: (M+H)+: 369.1
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([O:9]C)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:3]1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Temperature: 65 °C

Procedure:
To a solution of methyl (+−)-trans-4-methylene-2-phenylcyclopentanoate prepared as in Example 1, Step A (28.4 g, 131 mmol) in methanol (400 mL) was added 5N sodium hydroxide (131 mL, 656 mmol). The reaction was heated at 65° C. for 1 h then cooled and concentrated. The residue was diluted with water, acidified with 2M hydrochloric acid and extracted twice with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo to give the crude title acid (27.2 g) which was used directly in Step B.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=O)[O:17]CC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[NH:21]([C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22].O>CN1C(=O)CCC1>[OH:17][C:16]1[N:22]2[N:21]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:2]=[C:1]2[CH:3]=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)[N:15]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)NN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(O)n2n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.24 g (8.4 mmol) of ethyl hydrazino(oxo)acetate are dissolved in NMP (16 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and poured into water (100 ml), and the precipitate is filtered off, washed with water and diethyl ether and dried. 1.90 g (64% of theory) of the crude product are obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH2:25]([N:29]([CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CNCC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].[CH2:25]=[O:26].Cl>CCCCCC.O1CCCC1>[OH:26][CH2:25][C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: C=O
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CCO)cc2)CC1
Reaction time: 1 h

Procedure:
6.75 ml (10.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is saturated with formaldehyde, acidified by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:2) gives 1.80 g of 1-(hydroxymethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR7## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.94 g of 1-(fluoromethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene. ##STR8##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:33][CH2:34][CH3:35])=[C:17]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:18]=1>>[CH2:34]([O:33][C:16]1[CH:15]=[CH:14][C:13]([NH:12][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])=[CH:18][C:17]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH3:35]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 4-methyl-1-piperazinylsulphonyl chloride and 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure of Example 91, and was obtained as an orange powder (13%), m.p. 152-153° C. Found: C,54.32; H,6.38; N,19.88. C22H31N7O4S requires C,53.97; H,6.38; N,20.03%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH2:32][OH:33])[N:22]3[CH:21]=1)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[C:12](=[O:13])[NH:14][C:17](=[O:16])[C:18]=3[C:20]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=[CH:29]4)[CH2:25][CH2:24][CH:23]([CH2:32][OH:33])[N:22]5[CH:21]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2CO
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3CO)=C1c1c[nH]c2cc(F)ccc12

Procedure:
Beginning with 2-(6-fluoro-1H-indol-3-yl)acetamide and (4-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)(=[O:33])=[O:32])[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC1(C)C=Cc2cc(CNc3ccccc3)cnc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2cnc3c(c2)C=CC(C)(C)O3)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 19a (20 mg, 0.075 mmol) in DCM (1 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (36 mg, 0.150 mmol) and triethylamine (0.021 mL, 0.150 mmol). The reaction was stirred for 24 hours at room temperature. The reaction mixture was washed with water (×2) and the organic layer dried over MgSO4 and concentrated in vacuo. Column chromatography (2:1 hexane/EtOAc) gave a white solid (?? g). Yield: 43%. 1H NMR (CDCl3): δ 1.47 (s, 6H), 3.76 (s, 3H), 3.97 (s, 3H), 4.60 (s, 2H), 5.66 (d, 1H, J=9.6), 6.26 (d, 1H, J=10), 6.93-6.99 (m, 4H), 7.23-7.25 (m, 3H), 7.32-7.36 (m, 2H), 7.63 ppm (d, 1H, J=2.4). HRMS (ESI) m/z calcd for C25H25N2O5S [M+H)+] 467.1641. found: 467.1636. HPLC: ret. time=7.5 min, 99.0%