Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4C=CC=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.C[N:30]1[C:34](CO)=[N:33]C=N1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[N:24]([CH3:25])[N:33]=[CH:34][N:30]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: FCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Reactant: Cn1ncnc1CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cn1ncnc1COc1nn2c(-c3cc(CF)on3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from the product of Example 66 part c (150 mg, 0.5 mmol) and 2-methyl-1,2,4-triazole-3-methanol (61 mg, 0.53 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) using the procedure given in Example 1 using lithium bis(trimethylsilyl)amide (0.59 ml, 1.0M in tetrahydrofuran) as the base (80 mg, 43%), mp 250-252° C.; 1H NMR (360 MHz, d6-DMSO) δ 4.01 (3H, s, CH3), 5.76 (2H, d, J=47 Hz, CH2), 5.83 (2H, s, CH2), 7.70 (1H, d, J=Hz, Ar—H), 7.96 (1H, m, Ar—H), 8.02 (1H, s, Ar—H), 8.13 (1H, m, Ar—H), 8.25 (1H, d, J=7.8 Hz, Ar—H), 8.59 (1H, d, J=7.9 Hz, Ar—H);M1S (ES+) m/e 381 [MH]+; Anal. Found. C, 52.31; H, 3.36; N, 28.64. C17H13N8O2F.0.15CH2Cl2 requires C, 52.40; H, 3.41; N, 28.51%.
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].Br[C:14]1[C:15]([O:33][CH3:34])=[C:16]([C:22]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(B(CC)CC)C>>[C:27]1([S:26][CH2:25][C:22]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:33][CH3:34])[C:14]([CH2:1][CH3:2])=[CH:24][CH:23]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: CCc1ccc2c(c1)C(=O)OC2
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CSc2ccccc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 3-bromo-6-(phenylthiomethyl)-2-methoxybenzoate (Intermediate 73) and triethyl borane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].C(=O)([O-])O.[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>C(O)C>[C:8]([C:7]1[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Product: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1

Procedure:
To a suspension of 101 mg (0.30 mmol) (4S)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 6) in ethanol (2.43 ml) under argon atmosphere was added 52 μl (0.30 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 40 min. Subsequently, the solution was evaporated, and the residue was dried in vacuo. The precipitate was stirred in 1.5 ml THF/pentane (9:1 v/v) for 7 days and then centrifuged to yield 70 mg (51% of th.) of the title compound as a solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
40% Methanolic Triton B (0.07 mL, 0.15 mM) was added to a solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (60 mg, 0.13 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (30 mg, 0.19 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (86%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3500, 3350, 1727, 1642, 1291, 1236, and 772. MS (ES) m/e 515.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][OH:16].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][OH:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccnc2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 4,7-dichloroquinoline (50.0 g, 252 mmol) and of 2-aminoethanol (46.26 g, 757 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then at 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 250 ml of a 10%, w/v, aqueous sodium hydroxide solution. The precipitate obtained is filtered off through sintered glass, washed with water and then brought to reflux in 125 ml of methanol for 15 min. After returning to ambient temperature, the precipitate is filtered off through sintered glass, washed with 3 times 40 ml of methanol and then dried under vacuum. The product 5 is obtained in the form of a white powder: 52.28 g (yield=93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:20]1[CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22][CH2:21]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:20]2[CH:28]3[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21]2)=[O:9])[CH:3]=1
Reactant: C1CCC2NCCC2C1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.517 g (2.92 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane were combined with 1.07 mL (6.00 mmol) DIPEA. 0.73 g (2.92 mmol) octahydroindole in 10 mL DCM was slowly added dropwise. After 2 h stirring at RT the mixture was diluted with dichloromethane and extracted with water. The organic phase was separated off, dried on sodium sulphate, filtered, evaporated down i. vac. and dried.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:63])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH:47]([OH:62])[CH2:46]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:71][CH:72]=[CH2:73].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:63])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH:47]([O:62][CH2:73][CH:72]=[CH2:71])[CH2:46]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)C(F)C(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-20-fluoro-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexane is added 1.5 equivalents of allyl trichloroacetimidate, and the reagents are allowed to mix for 5 minutes. A catalytic amount of trifluoromethanesulfonic acid is then added slowly via syringe and the mixture is stirred at room temperature. After 3 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:15][CH2:16][C:17]1[S:18][C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:15][CH2:16][C:17]1[S:18][C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:22]([O-:6])=[CH:21][C:20]=2[N:29]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OCc1nc2cnc3ccccc3c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1nc2c[n+]([O-])c3ccccc3c2s1

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (34.7 grams (g) of 77% purity, 155 millimoles (mmol)) was added over a period of 15 minutes to a solution of [1,3]thiazolo[4,5-c]quinolin-2-ylmethyl acetate (U.S. Pat. No. 6,110,929, Example 37 Parts A and B, 20.0 g, 77.4 mmol) in chloroform (500 milliliters (mL)), and the reaction was stirred for two hours at room temperature and subsequently washed with aqueous sodium carbonate (500 mL of 10% weight/weight (w/w)). The organic layer was dried over magnesium sulfate and filtered to provide a solution of (5-oxido[1,3]thiazolo[4,5-c]quinolin-2-yl)methyl acetate in chloroform.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1c2ccc(O)cc2C2CCC(N)C21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1c2ccc(O)cc2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture was stirred for 2 hours, extracted with water, dried (Na2SO4) and concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethoxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=O)[CH3:19])[C:6]=1[O:7][CH:8]([CH3:13])C(OC)=O)=[O:4].Cl.O1CCOCC1>O>[CH3:13][C:8]1[O:7][C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:17][CH:16]=[CH:15][C:14]=2[C:18]=1[CH3:19]
Reactant: COC(=O)c1cccc(C(C)=O)c1OC(C)C(=O)OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c(C)c(C)oc12
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of 4.42 g of methyl 2-(2-methoxycarbonyl-6-acetylphenoxy)propionate, 20 ml of 6N hydrochloric acid and 20 ml of dioxane is refluxed for 10 minutes, and water is added to the reaction mixture. The aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is dissolved in 30 ml of tetrahydrofuran, and 5.55 ml of oxalyl chloride and a drop of dimethylformamide are added to the solution. The mixture is stirred for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in 100 ml of benzene. The solution is added dropwise to a refluxed solution of 6.66 ml of triethylamine in benzene and the mixture is refluxed for 5 hours. The reaction mixture is washed successively with 2% hydrochloric acid and water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=5:1) to give 1.48 g of methyl 2,3-dimethylbenzofuran-7-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21]([Cl:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=3)[CH2:13][CH2:12]2)[N:7]=[C:6]([Cl:31])[CH:5]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[Cl:31][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21]([Cl:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=3)[CH2:13][CH2:12]2)[N:7]=1)[C:3]([OH:32])=[O:2]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(=O)OC)cc(Cl)n3)CC2)cc(OCC)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(CN2CCC(Nc3cc(C(=O)O)cc(Cl)n3)CC2)cc(OCC)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of 2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinic acid methyl ester (0.17 g, 0.35 mmol, 1.0 equiv; example 224) in THF/methanol (2:1) (15 mL) was added a solution of 1 M LiOH (0.87 mL, 0.87 mmol. 2.5 equiv) drop by drop. After 16 h, the reaction mixture was poured into ice water, the pH of the water phase adjusted to 3-4 with diluted HCl and the mixture extracted twice with dichloromethane. The organic phases were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.12 g (73%) of the title compound as colorless solid. MS (ISP): 468.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([S:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:13])=[O:12])[CH2:21]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 89.7 %

Procedure:
A solution of 250 mg (1.06 mmol) of 4-nitrophenylmethanesulfonyl chloride and 133 mg (1.17 mmol) of cis-2,6-dimethylpiperazine in CH2Cl2 (10 mL) was treated with 325 μL (2.33 mmol) of triethylamine at RT for 20 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 298 mg (90%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.87 (d, 2H, J=8.8 Hz), 4.24 (s, 1H), 3.59-3.53 (m, 2H), 2.92-2.82 (m, 2H), 2.30-2.23 (m, 2H), 1.04 (d, 6H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H). found 314.1.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: Brc1cccnc1OC1CN(c2ccc3ccccc3n2)C1
Reactant: N#CC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#CC1CCN(c2cccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 100 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
A mixture of 2-(3-((3-bromopyridin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.9; 177 mg, 0.50 mmol), piperidine-4-carbonitrile (55 mg, 0.50 mmol), Pd2(dba)3 (22 mg, 0.025 mmol), 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (16 mg, 0.025 mmol) and t-BuONa (106 mg, 1.0 mmol) in toluene (10 mL) was stirred at 100° C. for 10 hours. The mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (30 mL). The combined filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (30% to 50% EtOAc in petroleum ether) and followed by purification by reverse phase HPLC (10% to 80% water/MeCN) to afford 1-(2-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyridin-3-yl)piperidine-4-carbonitrile (80 mg, 0.20 mmol, yield 40%). ESI-MS (M+1): 386 calc. for C23H23N5O 385.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:9]1[N:10]=[CH:11][C:12]([NH:15]C(=O)C(C)(C)C)=[N:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.NN.C(OCC)(=O)C>[C:1]([O:5][N:6]=[C:7]([C:9]1[CH:14]=[N:13][C:12]([NH2:15])=[CH:11][N:10]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=NOC(C)(C)C)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=NOC(C)(C)C)c1cnc(N)cn1
Temperature: 25 °C
Yield: 101606.6 %

Procedure:
A solution of N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (563.4 mg, 1.93 mmol) in dioxane (5.8 mL) and hydrazine monohydrate (9.6 mL) was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded 1-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime (408.4 g, quant.) as a light yellow solid: mp 113–115° C.; EI-HRMS m/e calcd for C10H16N4O (M+) 208.1324, found 208.1325.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH:5]([OH:32])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[C:22](=[O:27])[CH2:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:28](=[O:31])O[CH2:30][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2].[NH3:35]>C(O)C>[CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH:5]([OH:32])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[C:22](=[O:27])[CH2:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:28](=[O:31])[NH:35][CH2:30][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2]
Reactant: N
Reactant: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5c([nH]c4c21)C(=O)CC=C5)C(=O)OC3
Solvent: CCO
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5c([nH]c4c21)C(=O)CC=C5)C(=O)NC3

Procedure:
285 mg (0.63 mmol) (±)-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5,1-dioxoindolo-[2,3-a]furano[3,4-c]carbazole are heated in an autoclave for 6 hours at 140° C. in 30 ml of a saturated solution of ammonia in ethanol. The solution is evaporated, the residue is heated in 50 ml diisopropyl ether/tetrahydrofuran (4:1 v/v) and, after cooling, the crystals obtained are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl) -6,7,12,13-tetrahydro-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from 235° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([NH2:12])[CH3:11].[F:15][C:16]([F:28])([F:27])C1C=CC(CC(N)C)=CC=1>>[F:15][C:16]([F:28])([F:27])[C:6]1[CH:5]=[C:4]([CH2:9][CH:10]([NH2:12])[CH3:11])[CH:3]=[CH:8][CH:7]=1
Reactant: CC(N)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(N)Cc1ccccc1C(F)(F)F
Product: CC(N)Cc1cccc(C(F)(F)F)c1

Procedure:
According to the method used in Examples 1 to 14 but using 1-(2-trifluoromethylphenyl)-2-aminopropane, and 1-(4-trifluoromethylphenyl)-2-aminopropane, instead of 1-(3-trifluoromethylphenyl)-2-aminopropane, there were obtained the corresponding N-[1-(2-trifluoromethylphenyl) prop-2-yl] glycinates and N-[1-(4-trifluoromethylphenyl) prop-2-yl] glycinates.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][NH2:13]>CN(C)C=O.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(Cl)ccc1C(N)=O
Temperature: 60 °C

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (6.23 g, 32.6 mmol) and methylamine (98 mL of 2M in THF, 196 mmol) in anhydrous dimethylformamide (60 mL) was heated to 60° C. for 4 h. The reaction was then cooled to room temperature and diluted with water (800 mL) and extracted with ethyl acetate (4×600 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give a light orange oil (7.10 g). The oil was diluted with CH2Cl2 (300 mL) followed by the addition of silica gel (50 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (200 g, 230-400 mesh) and eluted with gradient 30-50% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound as a white solid (4.73 g, 78% isolated yield). TLC eluted with 50% EtOAc/hexanes and rendered with UV lamp gave Rf=0.5; 1H NMR 400 MHz (CDCl3) δ 7.47 (d, J=8.5 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1>>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
The title compound was prepared from tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4b) and (2-amino-1,3-thiazol-4-yl)acetic acid according to the procedure of Example 1, step A. The crude product was purified by preparative TLC plate eluting with 5% MeOH in dichloromethane to afforded the product (7.5 mg, 83%). m/z (ES) 637 (MH)+, 659 (MNa)+.