Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:33][O:34][CH3:35])=[O:27])[S:25][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:35][O:34][CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=3[CH:15]=2)[CH:23]=1)=[O:27]
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)OC)c(C)sc4c3)c2s1
Yield: 40 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (85.8 mg, 0.386 mmole) with 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (100 mg, 0.322 mmole) and Cs2CO3 (524 mg, 1.61 mmole) in a manner similar to that previously described for example 1 to give a brown solid (64 mg, 40%). 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (1H, d, J=4.90 Hz), 8.51 (1H, d, J=9.04 Hz), 8.15 (1H, s), 8.14 (1H, s), 7.54 (1H, dd, J=2.17, 8.95 Hz), 6.91 (1H, d, J=5.46 Hz), 4.47–4.38 (1H, m), 4.07–3.90 (2H, m), 4.03 (3H, s), 3.72–3.50 (2H, m), 3.42, 3.39 (3H, s), 2.94 (3H, s), 2.21–1.93 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=2.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.C(=O)(O)[O-].[Na+].C(=O)=O>C(O)(=O)C.O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]#[N:12])=[C:2]([N:1]3[CH:18]=[CH:22][CH:21]=[CH:20]3)[NH:3]2)=[CH:8][CH:7]=1)([O-:15])=[O:14]
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(-n2cccc2)[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14 h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased. The mixture is extracted with EtOAc (2×100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)(=O)C.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Reactant: C1CNCCN1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CN1c2ccccc2N=C(N2CCNCC2)c2cscc21

Procedure:
A mixture comprising 2.6 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 7), 8.6 g. of piperazine, 3 drops of acetic acid and 15 ml. of xylene is stirred and refluxed for 4 hours. The reaction mixture is evaporated, washed with water and the residue is dissolved in 50 ml. of 2N acetic acid. The solution is filtered, the filtrate is made alkaline with ammonium hydroxide and extracted with benzene. The extracts are dried over magnesium sulfate, filtered and evaporated producing an amber oil. This oil is dissolved in 20 ml. of ethanol and a mixture of 2.1 g. of fumaric acid in 40 ml. of ethanol is added. The solid is collected and recrystallized from 125 ml. of methanol giving the desired product as the fumarate salt, m.p. 205°-206° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:18]4[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:18]4[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCCO2
Product: Cl
Temperature: 25 °C
Yield: 14.4 %

Procedure:
To a solution of 0.51 mmol of 5-(1-(4-chlorophenyl)cyclo-butyl)-7-methoxy-2,3-dihydrobenzo[f][1,4]oxazepine in 5 ml methanol and 0.1 ml water were added 1.00 mmol sodium borohydride and the mixture was stirred at room temperature over night. The mixture was concentrated and the residue was dissolved in methylene chloride and water was added. The phases were separated using a Chromabond® PTS column. The aqueous phase was extracted with methylene chloride (1×). The combined organic phases were dried over Na2SO4, and filtered and concentrated to give 0.18 g of a crude material, which was purified by flash chromatography. To the combined fractions was added a solution of hydrogen chloride in 2-propanol and concentrated. The residue was dissolved in methanol and concentrated (2×). The material was further purified by flash chromatography to yield 14 mg of 5-(1-(4-chlorophenyl)cyclobutyl)-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride as a white solid (HCl-salt, 15%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cccc(N)c1C#N
Temperature: 35 °C

Procedure:
Sodium hydride (60% suspension in oil, 25.0 g, 0.625 mol) was suspended in anhydrous THF (1000 mL) under nitrogen and heated to an internal temperature of 40° C. to 45° C. 2-methylpropan-1-ol (61.2 mL, 0.661 mol) was then added slowly and portionwise. The mixture was heated at 40° C. to 45° C. for 1 hour, then cooled to 35° C. 2-amino-6-fluorobenzonitrile (50.0 g, 0.367 mol) was added and refluxed for 21 hours. The mixture was cooled to r.t., then ice (250 g), ice water (750 mL), and hexanes (1000 mL) was added. Insoluble solids were filtered out and the organic layer was separated. The aqueous layer was extracted once more with a mixture of diethyl ether (250 mL) and hexanes (250 mL). The combined organic layer was washed twice with a solution of citric acid (53 g) in water (500 mL), then washed with 80% brine (300 mL), then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (500 mL), and the immiscible oil carried through from the sodium hydride suspension was separated off in a separatory funnel. The solvent was evaporated under vacuum, and the residue was washed with hexanes (250 mL), after which the product 2-amino-6-isobutoxybenzonitrile was obtained as a viscous oil (46 grams, yield: 66%). 1H NMR (400 MHz, DMSO-d6) δ 7.16 (t, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 3.75 (d, J=7.2 Hz, 2H), 2.00 (m, 1H), 0.97 (d, J=6.8 Hz, 6H) ppm. MS 191 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.Cl>C1(O)CCCCC1.CCOCC>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([F:23])[CH:17]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1O
Agent: Cl
Solvent: CCOCC
Solvent: OC1CCCCC1
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1O
Temperature: 155 °C
Yield: 25.1 %

Procedure:
A solution of 4-chloro-6-hydroxy-7-methoxyquinoline (3.0 g, 14 mmol) and 4-chloro-2-fluoroaniline (3.5 g, 23 mmol) in cyclohexanol (100 ml) containing 1M ethereal hydrogen chloride (16 ml) was heated at 155° C. for 18 hours. After cooling the mixture was diluted with ether and isohexanes and the precipitate was collected by filtration. The crude product was dissolved in a mixture of methylene chloride/methanol/ammonia (100/10/1) and silica (10 g) was added. The solvent was removed by evaporation and the resulting powder was purified by flash chromatography eluting with methylene chloride/methanol/ammonia (95/5/1 increasing to 80/20/1) to give 4-(4-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinoline (1.12 g, 25%).
Reaction SMILES: O[CH2:2][C@H:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1.[F:25]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>O1CCCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[C:11]3[C@H:3]([CH2:2][F:25])[CH2:4][CH2:5][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CO)CC3)CC1
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CF)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
(R)-tert-Butyl 4-(5-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (30.0 mg, 0.0897 mmol) was dissolved in tetrahydrofuran (0.080 mL). Perfluoro-1-butanesulfonylfluoride (0.0644 mL, 0.359 mmol) and triethylamine trishydrofluoride (0.0584 mL, 0.359 mmol) were added to this solution, followed by triethylamine (0.150 mL, 0.726 mmol). The reaction mixture was allowed to stir for 12 hours at room temperature. The reaction was concentrated, and the material was subjected to chromatography on SiO2 and eluted with 10% MeOH/DCM. The desired 4-((R)-5-fluoromethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (25.0 mg, 83%) was isolated. LC/MS (APCI)+ m/z 337.2.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=O)[C:9](=[O:15])[NH:10]2.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: COc1cccc2c1C(=O)C(=O)N2
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1CC(=O)N2
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
Hydrazine monohydrate (265 mL, 5.46 mol) is added to a flask containing 4-methoxyisatin (484.26 g, 2.73 mol), sodium acetate (22.31 g, 0.27 mol) and dimethylformamide (2.4 L). The temperature rose from 19.2° C. to 31.9° C. within 5 minutes, and when the exotherm had ceased the solution is further heated to 110° C. over 40 minutes. Vigorous off-gassing is observed, and the temperature rose above the set point slowly. After 30 minutes the temperature stabilized at 110° C. and the gas evolution tapered off. The solution is kept at 110° C. for 40.5 hours at which point the heating mantle is removed and the solution is allowed to cool. At 40° C., the solution is seeded with 100 mg of 4-methoxyindole, and the contents are cooled to 17° C. with an ice bath. The resulting mixture is poured into water (6.2 L) which had been pre-cooled to 6° C. The flask is rinsed with water (600 mL), and the thick slurry is cooled to 4° C. before being filtered through polypropylene. The filter cake is rinsed with water (3×1.5 L) and the solid is dried in a 50° C. vacuum oven to provide 353 g of 4-methoxyindolin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23]C(OC1C=CN(C2C=CC(O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[N:46]([CH2:49][CH2:50]O)=[N+:47]=[N-:48]>>[F:23][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:50][CH2:49][N:46]=[N+:47]=[N-:48])=[CH:19][CH:20]=3)[C:11](=[O:22])[CH:10]=2)=[CH:3][CH:4]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Reactant: [N-]=[N+]=NCCO
Reactant: O=c1cc(OC(F)c2ccccc2)ccn1-c1ccc(O)cc1
Product: [N-]=[N+]=NCCOc1ccc(-n2ccc(OCc3ccc(F)cc3)cc2=O)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one and 2-(1-pyrrolidine)ethanol were replaced with 4-(4-(fluorobenzyloxy)-1-(4hydroxyphenyl)-1H-pyridin-2-one (Step (2) of Example 28) and 2-azidoethanol, respectively, to provide the title compound.
Reaction SMILES: O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([NH2:16])=[O:15].O.NN.CO.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([NH2:16])=[O:15])/[CH3:10])[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: NC(=O)CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C/C(=N\OCC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A microwave tube was charged with 2-(1,3-dioxoisoindolin-2-yloxy)acetamide (intermediate V) (166 mg, 0.76 mmol), hydrazine monohydrate (34.4 mg, 0.69 mmol) and 2 mL of methanol. It was heated at 95° C. for 12 h under microwave irradiation. After cooling, solid was removed by filtration and the solution was concentrated under reduced pressure. The residue was diluted with methanol, then 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (32 mg, 0.105 mmol) and 0.3 mL of acetic acid were added and the mixture was stirred at 40° C. overnight. After concentration, the residue was purified by prep-HPLC to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.33-8.27 (m, 2H), 7.98-7.95 (m, 2H), 7.78 (dd, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.31 (d, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 2.32 (s, 3H). LCMS (method A): [MH]+=376, tR=4.02 min.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:21]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:39][I:40]>>[I-:40].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([NH:29][C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH:21]=1)(=[O:18])=[O:19])[CH2:3][N+:2]([CH3:39])([CH3:1])[CH3:38])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1NC(=O)N1CCOCC1
Reactant: CI
Product: CCOc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)cc1NC(=O)N1CCOCC1
Product: [I-]

Procedure:
According to the method described in example S72b, (R)-benzyl 4-(dimethylamino)-3-(4-ethoxy-3-(morpholine-4-carboxamido)phenylsulfonamido)butanoate was reacted with methyl iodide to give the title compound as a white solid in quantitative yield. MS ESI 563.3 [M+H]+, calcd for [C27H38N4O7S+H]+ 563.25
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14](S(C)(=O)=O)[N:15]=1>C1COCC1.O>[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(OC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of cyclopentanol (0.287 g, 3.33 mmol) in THF (5 mL) was added sodium hydride (0.016 g, 0.67 mmol) and the mixture stirred at rt under a nitrogen atmosphere for 30 min. Then, the mixture was added treated with a solution of 4-chloro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.155 g, 0.67 mmol) dropwise in THF (2 mL) and the resulting mixture stirred at rt for 2 h. After this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0:080 g, 52%). MW=238.71. 1H NMR (CD3OD, 300 MHz) δ 5.64-5.40 (m, 1H), 2.90 (t, J=7.6 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.21-2.08 (m, 2H), 1.90-1.71 (m, 4H), 1.71-1.59 (m, 2H), 1.38-1.18 (m, 2H); APCI MS m/z 239 [M+H]+.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][C:20]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[O:37][CH3:38])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:41])=[CH:23][C:24]([CH3:40])([CH3:39])[NH:25]2)=O)(C)(C)C>>[NH2:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][C:20]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[O:37][CH3:38])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:41])=[CH:23][C:24]([CH3:40])([CH3:39])[NH:25]2
Reactant: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1NC(=O)OC(C)(C)C)C(C)=CC(C)(C)N2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1N)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4N HCl/1,4-dioxane solution (1 mL) was added to 5-(2-t-Butoxycarbonylaminophenoxymethyl)-6-(4-fluoro-2-methoxyphenyl)-2,2,4-trimethyl -1,2-dihydroquinoline (Compound No. 3-79, 9.6 mg, 0.019 mmol), then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added to the residue and separated. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the titled compound (5.4 mg) as a yellow oil. (Yield 70%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1>>[ClH:23].[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[O:27][CH2:26][CH2:25][CH2:24][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1
Reactant: COc1ccc(OCCCCl)cc1OC
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)CC2
Product: COc1ccc(OCCCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C3=O)C2)cc1OC
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3,4-dimethoxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[CH3:21][C:22]1[O:26][N:25]=[CH:24][CH:23]=1.CS[C:29]1[S:30][CH2:31][CH2:32][N:33]=1>C1COCC1>[NH2:25][C:24]1[N:33]2[CH2:32][CH2:31][S:30][C:29]2=[CH:21][C:22](=[O:26])[CH:23]=1
Reactant: Cc1ccno1
Reactant: CSC1=NCCS1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Nc1cc(=O)cc2n1CCS2
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a solution of lithium diisopropylamide (LDA), prepared from n-BuLi (106.6 ml, 0.16M) and diisopropylamine (16.7 g, 23.1 ml, 0.16M), in dry THF (100 ml) was added under N2 at -10° C., 5-methylisoxazole (6.8 g, 0.08M). The resultant yellow suspension was mechanically stirred at -10° C. for 30 min before the 4,5-dihydro-2-methylthiothiazole (11 g, 0.08M) was added dropwise. After the addition was complete, an orange oil separated, and the mixture was allowed to warm to ambient over a period of 20 hr. A mixture of MeOH (60 ml) and glacial acetic acid (4.5 ml, 0.08M) was slowly added and the resultant reddish solution was stirred at ambient overnight. The solvents were evaporated in vacuo, and the residual oil was flash column chromatographed on silica gel (EM-60) with 30% MeOH in CH2Cl2 as the eluent to give the desired amine (7 g), which was further recrystallized from MeOH/Et2O to give the title compound (5.4 g, 40%), mp>241° C. TLC (30% MeOH in CH2Cl2); Rf=0.33. IR (KBr) cm1, 3350-3000 (broad), 1675, 1625.
Reaction SMILES: N1CCC([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CC1.ClC1C=C(C=O)C(OC)=CC=1NC(=O)C=C.C(O)(=O)C>CC1CCCO1>[C:11]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:8](=[O:7])[OH:22]
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: C=CC(=O)Nc1cc(OC)c(C=O)cc1Cl
Solvent: CC1CCCO1
Solvent: CC(=O)O
Product: O=C(O)Nc1ccccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Biphenyl-2-ylcarbamic acid piperidin-4-yl ester (which may be prepared according to preparation 8 in WO 2004/074246A) (63.0 kg, 212.57 mol) was added to a stirred suspension of N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (which may be prepared according to Step C (Preparation 1) or C (Preparation 2)) (50.0 kg, 208.62 mol) and acetic acid (12.6 kg, 209.83 mol) in 2-methyltetrahydrofuran (430 kg) at 25° C. The mixture was then heated to 50° C. over 60 mins and held at this temperature for 2 hours. The resulting suspension was cooled to 20° C. over 90 mins and held at this temperature for 4 hours. The suspension was filtered under vacuum and the filter cake was washed with IMS (3×78.9 kg). The solid was dried in a vacuum oven at 50° C. for 10 hours to give biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-formyl-5-methoxyphenyl-carbamoylethyl]piperidin-4-yl ester as a white solid (90.7 kg, 80.6% th).
Reaction SMILES: [ClH:1].C1(C[N:9]2[CH2:14][CH2:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])([CH3:15])[CH2:11][CH2:10]2)C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[CH3:15][C:12]1([NH:16][C:17](=[O:19])[CH3:18])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1(C)CCNCC1
Yield: 91.2 %

Procedure:
A solution of 19 g of N-[1-(phenylmethyl)4-methyl-4-piperidinyl]acetamide hydrochloride in 400 ml of methanol was hydrogenated at normal pressure and at room temperature with 5 g of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 11.8 g of N-[4-methyl-4-piperidinyl]acetamide hydrochloride; mp. 230°-233° C. (interm. 3).
Reaction SMILES: B(O)O.Br[C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[F:13][C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1ccc(F)cc1-c1ccco1

Procedure:
4-fluoro-2-(furan-2-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 2-bromo-4-fluorobenzaldehyde and furan-2-ylboronic acid (20 mg, 94 mg theoretical, 21.3%). LC-MS m/z 191 (M+1).