Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1C=C[C:5]([CH:8](C)[C:9]([NH2:11])=O)=[CH:4][CH:3]=1.[Li].O.[OH-].[Na+].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:18][C:19]1[CH:2]=[CH:3][C:4]([CH2:5][CH2:8][CH2:9][NH2:11])=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(C)C(N)=O)cc1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CCCN)cc1

Procedure:
2-(4-Methylphenyl)propionamide (4 g) in dry tetrahydrofuran was added dropwise under nitrogen to lithium alumimium hydride (0.93 g) in dry tetrahydrofuran. The mixture was refluxed for 1 h at the end of addition. Water (1 ml), 2N. NaOH (1 ml), further water (3 ml) were added, the mixture filtered and the filtrate evaporated to give 3-(4-methylphenyl)propanamine (3.5 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17][N:18]([CH2:29][C:30]([O:32][CH3:33])=[O:31])S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+].CO.Cl>CS(C)=O.O>[CH3:33][O:32][C:30]([C:29]1[N:18]=[CH:17][C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][CH:8]=[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]=2)=[O:31]
Reactant: COC(=O)CN(Cc1cc(Oc2ccccc2)ccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 0 °C
Yield: 73 %

Procedure:
To a mixture of 2-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-4-phenoxy-benzoic acid methyl ester (14.0 g, 28.1 mmol) in DMSO (56 mL) was slowly added 30% NaOMe in MeOH (15.3 mL, 84.3 mmol). The resultant mixture was stirred at room temperature for 30 min and poured into 200 mL of ice and water. It was slowly acidified by conc. HCl aq. solution (10 mL) and then extracted with EtOAc. Organic layer was washed with 3% NaHCO3 solution, water and brine, and was dried over Na2SO4, filtered and concentrated. Crude produce was purified by silica gel chromatography to provide the title compound 6.05 g (20.5 mmol) in 72.9% yield. 1H NMR in CDCl3, δ in ppm: 11.7 (s, 1H), 8.59 (s, 1H), 8.36 (d, 1H, J=9.2 Hz), 7.55-7.1 (m, 7H), 4.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][C:14]3([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]3)[CH2:13][CH2:12]1)[C:7](=[O:24])[C:6]([C:25](OCC)=[O:26])=[C:5]2[OH:30].Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][C:14]3([O:21][CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][O:17]3)[CH2:15][CH2:16]1)[C:7](=[O:24])[C:6]([C:25]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])=[C:5]2[OH:30]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(C)COC2(CCC3(CC2)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc23)OC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of ethyl 6″-chloro-4″-hydroxy-5,5-dimethyl-2″-oxo-dispiro[1,3-dioxane-2,1′-cyclohexane-4′,1″-naphthalene]-3″-carboxylate (69 mg, 159 μmol) and tert-butyl 2-aminoacetate hydrochloride (53 mg, 317 μmol) in 1.5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (62 mg, 476 μmol). The mixture was warmed to 95° C. and stirred for 2 hours, M+1=420. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 66 mg of the title compound as a white yellow solid. MS (m/z)=520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:39][C:35]([CH3:38])([CH3:34])[CH2:36][NH:37][C:29]([C:26]1[CH:27]=[CH:28][C:20]2[C:19]3[S:32][C:16]([C:14]([N:13]([C:3]4[CH:4]=[CH:5][C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])[CH3:33])=[O:15])=[CH:17][C:18]=3[CH2:24][CH2:23][O:22][C:21]=2[CH:25]=1)=[O:30]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCC(C)(C)N)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 340 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.3
Reaction SMILES: [ClH:1].O=C1C2C3C(=CC=CC=3C(=O)N1CCCC[N:21]1[CH2:26][CH2:25][CH:24]([N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]1)C=CC=2.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[C:53](=[O:54])[C:52]2[CH:55]=[CH:56][CH:57]=[C:50]3[C:51]=2[C:46](=[CH:47][CH:48]=[CH:49]3)[C:45]1=[O:58].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:58]=[C:45]1[C:46]2[C:51]3[C:50](=[CH:57][CH:56]=[CH:55][C:52]=3[C:53](=[O:54])[N:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:21]1[CH2:22][CH2:23][CH:24]([N:27]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:25][CH2:26]1)[CH:49]=[CH:48][CH:47]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: CCC(=O)N(c1ccccc1)C1CCN(CCCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1

Procedure:
Following the procedure of part (b) of example 31 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains N-[1-[5-(1,3-dihydro- 1,3-dioxo-2H-benz[de]isoquinolin-2-yl)pentyl]-4-piperidinyl]-N-phenylpropanamide, hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][S-:12].[Na+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(F)ccc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(SC)ccc1Br
Temperature: 65 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methoxybenzene (10.0 g) in DMF (100 mL) was added sodium methanethiolate (4.44 g). The mixture was stirred at 65° C. for 2 h. The mixture was cooled to 0° C. and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h and further sodium methanethiolate (4.44 g) was added. The mixture was stirred at 65° C. for 1 h. The mixture was cooled to 0° C. and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 6.2 g of the title compound as a 2:1 mixture with the starting material. The mixture was used for the next step without purification.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[O:8][N:7]=1)([CH3:5])[CH3:4])#[N:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[C:1]([C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([S:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:37]=2)=[O:20])[O:8][N:7]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
A mixture of phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 125A steps 1 through 3) (95 mg, 0.35 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.319 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and dried over magnesium sulfate. Concentration under reduced pressure gave a solid which was triturated with methanol to afford 1-(3-(2-cyanopropan-2-yl) isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (50 mg, 32%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ10.52 (brs, 1H), 9.14 (brs, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.36 (m, 3H), 6.28 (s, 1H), 3.99 (s, 6H), 1.68 (s, 6H); LC-MS (ESI) m/z 491 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])=[CH:6][C:7]=1[C:8]([NH2:10])=O>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])=[CH:6][C:7]=1[C:8]#[N:10]
Reactant: NC(=O)c1cc(-c2cccc(F)c2F)nnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(-c2cccc(F)c2F)nnc1Cl

Procedure:
3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carboxamide (3.03 g, 11.2 mmol) was stirred in phosphoryl chloride (30 mL) at reflux for 3 hours, cooled, and evaporated to dryness. The residue was dissolved in dichloromethane, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and evaporated to give the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:38])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30][Br:38])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(CBr)nc12
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A mixture of the product from Example 6, Step A (2380 mg, 5.73 mmol), NBS (1530 mg, 8.6 mmol), AIBN (94 mg, 0.57 mmol) in CCl4 (50 mL) was heated under reflux for 17 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by SiO2-gel chromatography using 30% EtOAc/hexanes to give the desired product (140 mg). API-MS: 492, 494 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.4 (t, 1 H), 7.2 (d, 1 H), 4.5 (s, 2 H), 5.15 (t, 2 H), 4.0 (s, 3 H), 2.6 (m), 1.8-1.0 (m), 1.4 (s, 9 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][NH2:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To 69a (6.93 g, 20 mmol) in 40 mL of DCM was added hydrazine hydrate (2.91 mL, 60 mmol). The mixture was stirred at room temperature for 4 h, cooled in an ice bath for 30 minutes, then filtered. The solid was rinsed with 10 mL of DCM and the filtrate was evaporated. After cooling in the fridge, more solid precipitated and the oil was dissolved in 10 mL of DCM and filtered. The filtrate was evaporated to give 4.31 g (99% yield) of 69b.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CCCCCC.O1CCCC1>[C:3]([CH2:5][C:6]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:4]
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
Sodium hydride (53% dispersion in oil) (5.17 g, 0.1 mole) was washed by decantation with hexane (2×150 ml), tetrahydrofuran (THF) (150 ml) and was finally suspended in THF (150 ml). Diethyl 2-(cyanomethyl)malonate (26.4 g, 0.11 mole) in THF (20 ml) was added dropwise over 45 minutes keeping the internal temperature at 18° C. to 22° C. (with ice bath cooling). The resulting suspension cleared over 15 minutes when 2-chloro-5-nitropyridine (14.22 g, 0.09 mole) was added to give a deep magenta solution. The resulting solution was refluxed for 3 hours and the solvent was removed on the rotary evaporator. The resulting oil was partitioned between water (200 ml) and chloroform (200 ml), the pH was adjusted to ~7 (concentrated hydrochloric acid), and the chloroform was run off. The aqueous layer was extracted with a further (2×250 ml) chloroform, the extracts were combined, dried over magnesium sulphate and the solvent was removed to give the title compound as an amber oil. Ether (25 ml) was added and the solution was allowed to crystallise to give the title compound (18.48 g). m.p. 66°-68° C.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1)=[O:6])[CH3:3]>CO.[OH-].[Pd+2].[OH-]>[CH3:3][C:2]([CH3:28])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)C=Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)CCc2ccccc2)cc1
Yield: 81.9 %

Procedure:
A solution of 204 mg (0.507 mmol) of Boc amine from Example 16 in methanol was stirred over 20% palladium hydroxide under an atmosphere of hydrogen overnight. The reaction mixture was then filtered and concentrated. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexane) gave 168 mg (82%) of the title compound as a white solid: 1H NMR (200 MHz, CDCl3) δ7.39-7.21 (m, 3H), 7.15-7.06 (m, 4H), 6.96 (d, 2H, J=8.1 Hz), 6.25 (s, 1H), 4.49 (br s, 1H), 3.35-3.24 (m, 4H), 3.18-3.05 (m, 2H), 2.72 (t, 2H, J=7.1 Hz), 1.40 (s, 9H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([C:12]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16](=[O:27])[N:15]([CH3:28])[C:14](=[O:29])[CH:13]=1)[NH2:11]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:12]3[NH:10][N:11]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:13]=3[C:14](=[O:29])[N:15]([CH3:28])[C:16]2=[O:27])=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 414 %

Procedure:
Phenyl isothiocyanate (3.9 mL, 32.7 mmol) is added to a suspension of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (0.45 g, 1.6 mmol) in DMF (12 mL). The reaction mixture is heated at 120° C. for 40 hours, and then evaporated to remove solvent under reduced pressure. The residue is washed with hexanes, and then treated with MeOH (125 mL), and stored at −15° C. for 2 days to give a crystalline solid. The solid is recrystallized from CH3OH-EtOAc to afford 2.5 g of product (Yield: 61%). 1H NMR (400 MHz, DMSO-d6) δ 3.21 (s, 3H), 3.73 (s, 3H), 5.01 (s, 2H), 6.88-7.36 (m, 9H). MS (FAB) m/z 378.3 [M+H]+.
Reaction SMILES: C=O.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][CH2:9][NH2:10].[CH3:11]N(C)C=O.Cl>>[O:3]1[C:4]2[CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:6]=[CH:7]1
Reactant: NCCc1ccco1
Reactant: CN(C)C=O
Agent: C=O
Agent: Cl
Product: c1cc2c(o1)CCNC2
Reaction time: 0.25 h
Yield: 27 %

Procedure:
3.7 g (46 mmole) of a 37% aqueous formaldehyde solution were added dropwise at room temperature to 5.1 g (46 mmole) of 2-furylethylamine [the compound described, for example, in Brit., J. Pharmacol., 9, 376 (1954)], and the resulting mixture was stirred for about 15 minutes, after which it was extracted with diethyl ether. The organic extract was washed with water and dried over anhydrous sodium sulfate, and then the diethyl ether was removed by distillation under reduced pressure. 5 ml of dimethylformamide were added to the residue, and the resulting solution was added dropwise to 15 ml of dimethylformamide containing 3.6 g (100 mmole) of dry hydrogen chloride at room temperature. The resulting mixture was then stirred for 3 hours. At the end of this time, the greater part of the dimethylformamide was removed by distillation under reduced pressure, and then water and a 0.1N aqueous solution of sodium hydroxide were added to the residue so as to adjust its pH to a value of about 11; the mixture was then extracted with chloroform. The organic extract was washed with water and dried over anhydrous sodium sulfate. The chloroform was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 50:1 by volume mixture of chloroform and methanol as the eluent, to give the title compound as a brown oil in a yield of 27%.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][CH:22]([F:28])[C:23](OCC)=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[CH:22]([F:28])[F:21])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of diisopropylamine (12.7 g, 17.9 ml, 126 mmol) and tetrahydrofuran (375 ml) was cooled to −78° C. and n-BuLi (1.6 M in hexane) (78.6 ml, 126 mmol) was added dropwise. After stirring for 10 min commercially available 1-bromo-4-fluorobenzene {CAS[460-00-4]} (20 g, 12.4 ml, 114 mmol) was added dropwise at max. −60° C. Stirring was continued at −70° C. for 2.5 hours. Then ethyl difluoroacetate (17.0 g, 13.7 ml, 137 mmol) was added dropwise and the mixture was warmed to −10° C. and then quenched by pouring the mixture onto 1 M HCl. The mixture was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and evaporated to give a yellow liquid (34 g; 118%). The residue was chromatographed on 200 g silica gel with cyclohexane/ethyl acetate 3:1 to give 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (26.5 g, 105 mmol, 91.6% yield) as a yellow liquid. MS (EI): m/z=252.0 [M]+ and 254.0 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>C(Cl)Cl.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][C:26](=[O:27])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(NC(=O)CNC(=O)OC(C)(C)C)ccc21
Yield: 65.2 %

Procedure:
To a solution of 3-amino-9-ethylcarbazole (8.1 g, 38 mmol), tert-butoxycarbonylamino-acetic acid (6.7 g, 38 mmol), and N,N-dimethylaminopyridine (5.7 g, 46 mmol) in CH2Cl2 (125 mL) was added EDC (5.5 g, 46 mmol). The resultant solution was stirred at room temperature for 2 days, and then diluted with ethyl acetate (500 mL) and washed with aqueous 1 M HCl (2×100 mL), water (100 mL), saturated aqueous NaHCO3 (100 mL), and then brine (100 mL). The organic layer was then dried (Na2SO4), concentrated under reduced pressure, and then flash chromatographed (silica, 1:39 to 1:19 to 1:9 ethyl acetate/CH2Cl2) to afford [(9-ethyl-9H-carbazol-3-ylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (9.1 g, 65%) as a brown foam. MS m/z @ 368 (M+1).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:38](O)[CH:39]([CH3:41])[CH3:40].CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:38]([O:27][C:26](=[O:28])[CH2:25][O:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=2)[CH2:21][CH2:20]1)[CH:39]([CH3:41])[CH3:40]
Reactant: O=C(O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Reactant: CC(C)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)COC(=O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid (compound 235, 0.5 g, 0.84 mmoles) dissolved in THF (20 ml). To this solution cooled at 0° C. were successively added isobutanol (0.155 ml, 1.68 mmoles), DMAP (0.01 g, 0.084 mmoles) and EDCI (0.177 g, 0.93 mmoles). The reaction mixture was stirred for 2 hours at 0° C. and then allowed to reach room temperature and stirred overnight. The organic solution was washed with HCl 0.1N and water, dried over MgSO4 and concentrated. The resulting oil was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 99.5/0.5/0.1 v/v/v) to yield (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid isobutyl ester (compound 287, 390 mg, 65%) which was converted into its dihydrochloride monohydrate salt by reaction with HCl in diethylether.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]1[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the t-butyl ester from Step 1 (0.52 g, 0.0022 mole) in dichloromethane at 0° C. was added trifluoroacetic acid and the mixture stirred at rt for 30 min. The reaction was concentrated in vacuo to give the title compound as an oil. Analysis of the acid by chiral HPLC (Chirapak AD, 250×4.6 mm) using 95/5(A/B), 0.2% trifluroacetic acid in hexane(A) and ethanol(B), 1 mL/min, showed the material to have a purity of ≧94% EE. M.S.(M+1): 181.