Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Li+].N.[CH3:4][O:5][C:6]1([CH2:13][CH2:14][C:15]#[CH:16])[CH:10]=[CH:9][CH:8]([O:11][CH3:12])[O:7]1.Br[CH2:18][CH2:19][CH2:20][C:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23]>O1CCCC1>[CH3:4][O:5][C:6]1([CH2:13][CH2:14][C:15]#[C:16][CH2:18][CH2:19][CH2:20][C:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])[CH:10]=[CH:9][CH:8]([O:11][CH3:12])[O:7]1
Reactant: C#CCCC1(OC)C=CC(OC)O1
Reactant: COC(CCCBr)(OC)OC
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Yield: 108.2 %

Procedure:
To a stirred mixture of 0.51 g of lithium amide and ml of liquid ammonia was added dropwise a solution of 3.64 g of 2,5-dihydro-2,5-dimethoxy-2-(3-butynyl)furan in 2.5 ml of tetrahydrofuran during 5 minutes. The mixture was stirred under reflux for 30 minutes and then treated dropwise with a solution of 5.0 g of 1-bromo-4,4,4-trimethoxybutane (U.S. Pat. No. 3,864,387) in 5 ml of tetrahydrofuran during 5 minutes. This solution was stirred under reflux for one hour, the ammonia allowed to evaporate during one hour and the resulting solution stirred at 20° C. for 10 minutes. This solution was partitioned with ether and brine. The organic layer was dried, treated with 2 drops of pyridine, and then concentrated, giving 7.1 g of the desired compound as a light amber oil; PMR δ 5.9 (2H, m, vinyl hydrogens).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[N:15]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)cc1
Yield: 58.5 %

Procedure:
NaB(OAc)3H (43.4 g, 0.21 mol) was added in portions during 30 min to a mixture of pyrrolidine (17 mL, 0.21 mol) and 4-hydroxybenzaldehyde 1 (20 g, 0.16 mol) in CH2Cl2 (200 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 3 h and cooled. Then 10 N NaOH (20.5 mL) and water (300 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (3×200 mL). The organic fractions were evaporated. The residue was dissolved in water, concentrated HCl (15 mL) was added, and the mixture was extracted with ether (3×200 mL). The organic fractions were discarded. The aqueous layer was alkalized with 10 N NaOH (16 mL) and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with brine, dried with Na2SO4, and evaporated. The title compound (16.6 g, 57%) was obtained as yellow crystals. 1H NMR-data (DMSO-d6): 9.18 (br.s, 1H, OH); 7.00 (d, 2H, Ph, J=8.6 Hz); 6.68 (d, 2H, Ph, J=8.6 Hz); 3.43 (s, 2H, CH2); 2.33-2.42 (m, 4H); 1.62-1.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.[C:25]([O:31][CH2:32]CCl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:25]([O:31][CH2:32][N:22]1[N:23]=[N:24][C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:13]=3)[CH:19]=2)=[N:21]1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C(=O)OCCCl
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), chloroethyl pivalate and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 1.10 (9H, s), 5.41 (2H, s), 6.70 (2H, s), 7.28-7.30 (1H, m), 7.38-7.40 (2H, m), 7.52-7.54 (1H, m), 7.81-7.83 (3H, m), 7.94 (1H, s), 8.51 (1H, s), 8.68 (1H, d, J=5.1 Hz). [M+H] Calc'd for C22H22ClN7O2, 452. Found, 452.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=[CH2:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccccc1
Product: CC=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Yield: 74 %

Procedure:
To a solution of 10.0 g (24.0 mmole) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate concentrated in vacuum to a brown oil. Column chromatography on silica gel with methylene chloride as eluant gave 7.2 g of the title compound as a mixture of E and Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106° C.) by evaporation of a pure E isomer-containing fraction.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:20][O:21][CH3:22])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:1]([NH:8][C@@H:9]([C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][O:21][CH3:22])=[O:3]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of acetic anhydride (262 mg, 2.56 mmol) and (R)-2-amino-N-benzyl-3-methoxypropanamide 1.6 TFA (1000 mg, 2.56 mmol) in 10 mL of DCM and triethylamine (3.6 mL, 25.6 mmol) was added. The resulting solution was stirred at room temperature for three hours. DCM (200 mL) was added to the reaction mixture. The resulting solution was washed with H2O (200 mL), 0.2 N HCl (100 mL), 5% NaHCO3 (100 mL), and then H2O (100 mL) and dried over Na2SO4. A white solid was obtained after the solvent was removed under reduced pressure. The crude product was purified by crystallization from ethyl acetate/hexane (1:1). The desired product was obtained with a purity of 99% (220 mg, yield: 33.0%). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H). 3.39 (s, 3H), 3.45 (t, 1H), 3.84 (m, 1H), 4.48 (s, 2H), 4.56 (m, 1H), 6.44 (br., 1H). 6.74 (br., 1H), 7.28 (m, 3H), 7.36 (m, 2H). LC-MS (m/z) calculated 250.1. Found 251.1 [M+H]+, 273.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:10][C:2]([CH3:1])([CH2:3][C:4](=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: c1ccccc1
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(CC(=O)O)CC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3,3-dimethylglutaric anhydride (10.0 g, 70.4 mmol), anhydrous aluminum chloride (23.5 g, 176 mmol) and benzene (100 ml) was heated under reflux for 5 hours. The reaction mixture was poured into ice water, adjusted to pH 1 with a 35% hydrochloric acid and then extracted with ethyl acetate. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 17.4 g of 3,3-dimethyl-5-oxo-5-phenylpentanoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-chlorobenzene (0.69 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.84 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH:14]=[CH2:15])[CH:5]=1.[CH3:17]I>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:17])=[C:6]([CH2:13][CH:14]=[CH2:15])[CH:5]=1
Reactant: CI
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1O
Product: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reaction time: 16 h
Yield: 96 %

Procedure:
3-Allyl-4,5-dimethoxybenzoic acid methyl ester was prepared from 3-allyl-4-hydroxy-5-methoxybenzoic acid methyl ester (Example 1, Step 2) by following Method C using methyl iodide as alkylating agent. The reaction was conducted at room temperature for 16 h and crude product was purified by flash column chromatography (96% yield).
Reaction SMILES: COC([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[C:6]=1[OH:25])=O.O.[OH-].[Na+]>CN(C)C=O>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]3[C:6](=[O:25])[CH2:5][O:16][C:15]=3[C:14]=2[CH:13]=1
Reactant: COC(=O)c1oc2c3cc(OC)ccc3n(-c3ccccc3)c2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c1c(n2-c2ccccc2)C(=O)CO1
Yield: 47.1 %

Procedure:
A mixture of 39.0 g (0.12 mole) of 3-hydroxy-7-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic methyl ester (Preparation described in U.S. patent application Ser. No. 369,448 now issued as U.S. Pat. No. 4,503,236) in 195 ml of N,N-dimethylformamide and 80 ml of water was treated with 40 ml of 50% aqueous sodium hydroxide, After heating on the steam bath for two hours, the product was isolated as described in Example V above. Recrystallization from 2-methoxyethanol/N,N-dimethylformamide yielded 15.8 g (49% yield) of the product, mp 175° C.-dec. An additional recrystallization as above raised the mp to 185°-187° C.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([O:28]C)=O)[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1>CCO>[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([NH:2][NH2:3])=[O:28])[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Yield: 76 %

Procedure:
Hydrazine monohydrate (1 mL, 20.6 mmol) was added to a suspension of methyl [3-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate (Example 1); 221 mg, 0.53 mmol) in EtOH (10 mL) and heated to reflux for 20 hours. On cooling the mixture was concentrated under reduced pressure and H2O (20 mL) added and the white precipitate filtered off and dried in vacuo to give the title product (169 mg, 76%) as an off white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:14][C:15]2[C:16]([Br:22])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[CH3:23][Mg]Br>C1COCC1.C(OCC)C>[Br:22][C:16]1[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([C:1]([OH:3])([CH3:23])[CH3:2])[CH:5]=2)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Temperature: -78 °C

Procedure:
365 mg (0.86 mmol) of 3-acetyl-N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-benzenesulfonamide was dissolved in 3 mL of anhydrous THF and cooled down under nitrogen atmosphere to −78° C. To that solution 0.86 mL of 3M methylmagnesium bromide solution in diethyl ether was added dropwise. The solution was allowed to warm up to 0° C. and was then quenched with aqueous ammonium chloride and extracted with DCM. The organic layer was evaporated under reduced pressure and purified on silica using 5-40% ethyl acetate in hexanes to yield 288 mg of a white solid. LC-MSD, m/z for C14H13BrCl2N2O3S [M+H]+=438.9, 440.9, 442.9.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:9]>O.C(O)(=O)C>[CH2:6]([O:7][C:8](=[O:9])[C:10](=[N:1][OH:3])[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of sodium nitrite (56.5 g, 0.815 mol) in water (400 mL) was added to a solution of ethyl benzoyl acetate (120 g, 0.625 mol) in glacial acetic acid (300 mL) at 0-10° C. over a period of 2 h. The product started precipitating during the course of addition and the reaction mixture was warmed to room temperature and stirred for 30 min. Water (2.5 L) was added and the mixture was stirred for a further 30 min and then filtered under suction. The solid was washed with water (20 mL), petroleum ether (200 mL) and then dissolved in chloroform (700 mL). The filtrate was extracted with chloroform (2×100 mL) and the combined organic phase was washed with water (2×200 mL), brine solution (2×250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (122.5 g, 88%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:36][CH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:36][CH2:37][CH:38]4[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:39]4)[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CC(C)(C)OC(=O)N1CC(CCI)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 155 mmol), tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (68 mg, 219 μmol.41) and Cs2CO3 (203 mg, 622 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (40 g column, 50 μm silica-gel from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (103 mg, 155 μmol, 99.5%) as a white solid. MS (M+Na)+=688; 1H NMR (CDCl3) δ: 9.24 (s, 1H), 8.56 (dd, J=8.7, 5.3 Hz, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 6.98-7.16 (m, 2H), 5.75 (s, 2H), 4.46 (t, J=6.4 Hz, 2H), 4.02 (t, J=8.3 Hz, 2H), 3.49-3.72 (m, 5H), 2.49-2.69 (m, 1H), 2.33 (q, J=6.8 Hz, 2H), 1.65 (s, 9H), 1.48 (s, 2H), 1.45 (s, 9H), 0.92-1.03 (m, 2H), 0.00 (s, 9H); LCMS ESI+ TIC MS showed 100% purity, [M+Na]+=688.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:17])=[O:16]
Reactant: OCCCc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1c[nH]c2ccccc12

Procedure:
3-(3-Indolyl)-1-propyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (170 mg, 81%) from 3-(3-indolyl)-1-propanol (145 mg, 0.83 mmol) and methanesulfonyl chloride (142 mg, 1.24 mmol). 1H NMR (CDCl3, 300 MHz) δ2.17 (qu, 2H, J=7.3 Hz), 2.92 (t, 2H, J=7.0 Hz), 2.99 (s, 3H), 4.27 (t, 2H, J=6.4 Hz), 7.04 (d, 1H, J=2.2 Hz), 7.12 (dt, 1H, J=1.1, 7.0 Hz), 7.21 (dt, 1H, J=1.1, 7.0 Hz), 7.38 (d, 1H, J=8.1 Hz), 7.59 (d, 1H, J=7.3 Hz), 8.00 (br, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([O:35]C)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].[OH-].[Li+].O.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([OH:35])=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O

Procedure:
4-(4-Cyano-2-methoxycarbonyl-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 9)(3.39 g, 6.76 mmol) and lithium hydroxide (194.4 mg, 8.11 mmol) are stirred in 1,4-dioxane (84 ml) and water (6.0 mL) at room temperature for 100 h. Water is added and the mixture is acidified with hydrochloric acid (4.0 mol/L) to a pH value of 3. The aqueous phase is extracted with dichloromethane three times. The combined organic phase is dried over MgSO4, concentrated and purified by reversed phase HPLC. Yield: 1.34 g. ESI mass spectrum: [M+H]+=488; Retention time HPLC: 1.08 min (HPLC method Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCC(O)CO)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCC(O)CO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 75 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.183 mmol) in DMF (2 mL) were added PdCl2(PPh3)2 (15 mg), CuI (2 mg), trimethylsilyl acetylene (Aldrich, 2 mL) and Et3N (Aldrich, 2 mL) and the mixture was purged with nitrogen and then heated at 75° C. for 3 hrs. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by chromatography (0-4% MeOH in EtOAc). Yield 8 mg. MS (H+), 623
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH:4]([OH:32])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:31])[O:28][C:29](=O)[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[NH3:34]>>[CH3:33][N:2]([CH3:1])[CH2:3][CH:4]([OH:32])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:31])[NH:34][C:29](=[O:28])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)OC3=O
Reactant: N
Product: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)NC3=O

Procedure:
750 mg (1.7 mmol) (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxoindolo[2,3-a]furano[3,4-c]carbazole are heated in an autoclave with 50 ml ammonia-saturated ethanol for 20 hours at 140° C. The undissolved product is filtered off and again crystallised from ethanol. (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a yellow amorphous powder; m.p. 260°-270° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:24][CH3:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])C1C=CC=CC=1.Br.[OH-].[Na+]>CC(O)=O.O>[CH2:24]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH2:13][CH2:12][CH2:11][NH2:10])[CH3:25]
Reactant: CCN(CCCNC(=O)OCc1ccccc1)Cc1ccccc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CCCN)Cc1ccccc1OC
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of {3-[ethyl-(2-methoxy-benzyl)-amino]-propyl}-carbamic benzyl ester acid (1.4 g; 3.9 mmol) in 15 ml of glacial CH3COOH, 3.5 ml of a 33% solution of HBr in CH3COOH was added cautiously. It was left in agitation for 2 h, then the hydrobromate was precipitated with 100 ml of diethyl ether. The white solid formed was solubilised in H2O, basified with NaOH 2N and extracted with CHCl3 (5×20 ml). The anhydrified organic phase was evaporated in a vacuum to give 0.87 g of the compound XI as pure transparent oil on TLC (eluant CHCl3/MeOH/NH4OH 9.0:1.0:0.1); quantity yield; 1H NMR (free base; CDCl3) δ: 1.07 (t, 3H), 1.50 (s enlarged, 2H exchangeable with D2O), 1.57-1.71 (m, 2H), 2.55 (q, 4H), 2.73 (t, 2H), 3.60 (s, 2H), 3.84 (s, 3H), 6.83-6.99 (m, 2H), 7.19-7.44 (m, 2H).