Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2C(C)=CC=C2C)=[N:6][C:7]=1[CH3:8].Cl.NO.C(O)C>O>[NH2:9][C:5]1[N:4]=[C:3]([NH:16][C@@H:17]2[CH2:18][CH2:19][C@H:20]([O:23][CH2:24][CH2:25][OH:26])[CH2:21][CH2:22]2)[C:2]([Br:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1nc(N)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Yield: 69.4 %

Procedure:
A solution of 2-(cis-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol (1.23 g, 2.91 mmol) and hydroxylamine hydrochloride (1.01 g, 14.5 mmol) in 10:1 ethanol:water (22.0 mL) was heated to reflux overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-4%) to afford the title compound (697 mg, 70%).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[O:13]=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:13])[C@H:5]([OH:6])[C:3]([C:2]([OH:8])=[O:1])=[O:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
In particular, the process of the invention may be applied to a methanolic solution of ascorbic acid or sodium ascorbate produced by esterification of 2-keto-L-gulonic acid in methanol, followed by cyclization with sodium bicarbonate to produce a feed composition to the solvent exchanger to produce an aqueous product of ascorbic acid or sodium ascorbate. The product may then be obtained from the aqueous stream by crystallization.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2]>N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=O.CO>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Solvent: CO
Product: C#Cc1ccc(O)cc1
Reaction time: 3 h
Yield: 20.5 %

Procedure:
To 501.8 g of the same p-vinylphenol fraction as used in Example 5, obtained by vacuum flash distillation were added 149.0 g of methanol and 4.5 g of dimethyl 2,2′-azobis(2-methylpropionate). A polymerization reaction was conducted at 100° C. for 3 hours to obtain 101.0 g of a poly(p-vinylphenol). The polymer had a Mw of 9,500, a Mn of 5,300, a light transmittance at 248 nm, of 74.0% and a light transmittance at 450 nm, of 94.8%.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:17]=[N:18][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:27]>C(O)C.[Pd]>[ClH:27].[C:19]1([C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=[CH:17][N:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3ncnc(-c4ccccc4)c3CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2ncnc3c2CCNCC3)cc1
Temperature: 80 °C

Procedure:
Palladium charcoal was added to 17 g 7-benzyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine in 250 mL ethanol and 54 mL 1 M HCl solution. The reaction was stirred at 80° C. and 5 bar hydrogen. The mixture was filtered and evaporated to give 13.1 g of the desired product.
Reaction SMILES: [N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.[OH-].[Li+].C1COCC1>O>[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2Cc2ccccc21
Yield: 98.8 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimid-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (0.17 g, 0.36 mmol), lithium hydroxide monohydrate (0.042 g, 1 mmol), THF (3 mL), and water (10 mL) was stirred at room temperature for 20 hr, then was concentrated. The residue was dissolved in water, and the solution was brought to pH 4 with 3 N HCl. The resulting solution was kept in the refrigerator overnight, then the supernatant was decanted away from the solid. The solid was dried in vacuum to give the title compound (0.145 g, 91%) as a tan solid: MS (ES) 408.3 (M+H)+. Anal. Calcd for C24H29N3O3.1.3 HCl: C, 63.37; H,6.71; N, 9.23. Found: C, 63.67; H, 6.84; N, 9.46.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cccnc1Br
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromo-3-methylpyridine
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH:20]=[CH:21][C:22]([O:24]C)=[CH:23][C:18]=3[O:17][N:16]=2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=3[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 210 °C
Reaction time: 1.25 h

Procedure:
A mixture of 60 g of pyridine hydrochloride and 12.0 g 3-(4-chlorophenyl)-6-methoxy-1,2-benzisoxazole is heated with stirring at 210° C. for 75 min. The hot reaction mixture is poured with vigorous stirring onto ice and the solid is filtered, dried, and recrystallized from toluene to afford 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 203° C.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:32][CH2:31][C:19]2([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][NH:21][C:20]2=[O:30])[CH2:18][CH2:17]1.Cl.[CH3:34][N:35]([CH2:37][CH2:38][Cl:39])[CH3:36]>CN(C=O)C>[ClH:39].[CH3:34][N:35]([CH3:36])[CH2:37][CH2:38][N:21]1[C:20](=[O:30])[C:19]2([CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)[CH2:32][CH2:31]2)[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(CCc1ccccc1-c1cccs1)CC2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CN(c2ccccc2)C2(CCN(CCc3ccccc3-c3cccs3)CC2)C1=O

Procedure:
To a heterogenous mixture of unwashed 60% NaH dispersed in mineral oil (96.5 mg, 2.41 mmol) in DMF (3 mL) was added 8-[2-[2-(2-thienyl)phenyl]ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (prepared as in Example 5) (208.8 mg, 0.500 mmol). The mixture was stirred until H2 gas evolution was observed to stop (30 min), then treated with N,N-dimethylaminoethyl chloride hydrochloride (158 mg, 1.10 mmol). The resulting reaction mixture was stirred for an additional 18 h under argon atmosphere. The reaction was quenched with aqueous NH4Cl (50 mL), and the crude product was extracted into CHCl3 (2×40 mL). The organic extracts were washed with H2O (5×50 mL), dried over Na2SO4, filtered and concentrated to a crude oil. The crude oil was washed with hexane (3×50 mL) to remove mineral oil, then purified by Tapered prep TLC (6% MeOH in CHCl3) to yield title compound as a free base. The free base was dissolved in CHCl3 (15 mL) and treated with 1.0 mL of 1N HCl in Et2O. HCL salt was precipitated by addition of Et2O, collected by filtration and dried in the vacuum oven at 60° C. for 18 h to yield the title compound as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)c(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Yield: 55.8 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3-chloro-4-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.1 g, 9.84 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 0.59 g, 14.76 mmol), iodomethane (1.22 mL, 19.68 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (1.81 g, 56%). MS m/z (rel. intensity, 70 eV) 273 (19), 228 (13), 187 (17), 133 (12), 57 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[Li]CCCC.Cl[Si:17]([CH3:28])([CH3:27])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][Si:17]([CH3:27])([CH3:28])[CH:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]1[CH3:26]
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(C)cc2Br)C(C)=C1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, to a solution of 13.9 g (69.5 mmol) of 2-bromo-4,6-dimethylaniline in 200 ml of THF, 27.9 ml of 2.5 M (69.5 mmol) nBuLi in hexanes were added at −50° C. This mixture was stirred for 2 hours at ambient temperature. The resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 15.0 g (69.5 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 100 ml of THF at 0° C. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 180-184° C./0.5 mm Hg. Yield 20.1 g (77%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[OH:19])=[O:13])=[CH:10][C:9]([CH3:22])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][S:7]2(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[O:19][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[O:13])=[CH:10][C:9]([CH3:22])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][S:7]2(=[O:23])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2Cl)C(=O)C(C)(C)CS3(=O)=O)c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2Cl)C(=O)C(C)(C)CS3(=O)=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
0.60 Gram (1.46 mmol) of 5-chloro-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,3,8-trimethylthiochroman-4-one-1,1-dioxide was dissolved in 7 ml of dicholoromethane. Separately, 0.25 g (1.81 mmol) of potassium carbonate was dissolved in 7 ml of water, and these two solutions were mixed. Then, 0.34 g(1.78 mmol) of p-toluenesulfonyl chloride was added. Further, a small amount (about 20 mg) of benzyltriethylammonium chloride was added, and the mixture was stirred at room temperature for about 15 hours. The reaction mixture was diluted with dichloromethane and water and separated into two phases, and an organic layer was washed with diluted hydrochloric acid, then with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 0.77 g of the resultant oil was purified by silica gel column chromatography (developer solution: n-hexane/ethyl acetate, 2:1 v/v) to give 0.67 g (yield 82% of the titled compound. Table 26 shows the structural formula of the titled compound, and Table 27 shows the physical property data thereof.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][C:30]4[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=4)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4ccoc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.9 g (6.5 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-indole and 1.9 g (7.1 mmol) 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up, 1.2 g (42% of yield) of the expected acid were obtained.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13]>>[OH:13][CH2:12][C:11]([NH:10][C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:9])([CH3:15])[CH3:14]
Reactant: O=C(O)C1CCCCC1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)C1CCCCC1

Procedure:
Prepared as in Example 24a from cyclohexanecarboxylic acid and 2-amino-2-methylpropan-1-ol as a colorless oil (15%). MS 200 (MH+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[O:18].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>C(O)C(N)(CO)CO.Cl>[C:1]([NH:4][C@H:5]1[C@H:11]([C@@H:10]([C@@H:9]([CH2:14][OH:15])[OH:8])[OH:13])[O:12][C:17]([OH:18])([C:16](=[O:21])[OH:20])[CH2:19][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O

Procedure:
A solution prepared by dissolving 22 g of N-acetylglucosamine and 11 g of pyruvic acid in 50 mM of Tris-HCl buffer (pH 7.5) containing 5 mM ATP and 5 mM MgCl2To the solution was added 15 mg of protein having renin binding activities obtained in example 3 and 500 unit of N-acetylneuraminic acid lyase, and the total volume of the solution was adjusted to 0.5 liter. The mixture was reacted at 30° C. for 48 hours. After the reaction, 12.4 g of N-acetylneuraminic acid was produced in the reaction mixture. Reaction product was isolated by ion-exchange chromatography with Dowex 11 (DOW CHEMICAL CO.). After concentration, 10.3 g of N-acetylneuraminic acid was obtained by lyophilization.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][CH:44]=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35].CO>ClCCl>[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]4[O:15][C:14]5[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=5[C:9]=4[N:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Reactant: c1ccc2c(c1)oc1c(N3CCNCC3)ncnc12
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC(=S)N2CCN(c3ncnc4c3oc3ccccc34)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinobenzofurano[3,2-d]pyrimidine (200 mg, 0.79 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene; and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 150 mg (37%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:19]([C:15]1[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccccn1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccnc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.1 %

Procedure:
To a freshly prepared solution of lithium diisopropylamide (22 mmol) in dry THF (20 mL) under nitrogen and cooled to −78° was added a solution of 2-fluoropyridine (1.94 g, 20 mmol) in dry THF (10 mL). The reaction was stirred for 2.5 h at −78° before adding a solution of N-methoxy-N-methyl benzamide (3.47 g, 21 mmol) in THF (8 mL). The reaction mixture was allowed to warm to room temperature over 1.5 h and stir at room temperature for 1 h. The reaction was quenched with water (50 mL), extracted with EtOAc (2×50 mL), the extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (5–20% EtOAc in isohexane) to give the title compound as a colourless oil (1.05 g, 26%). δH (CDCl3) 8.44 (1H, ddd, J 4.9, 2.0, 1.1 Hz), 8.06 (1H, ddd, J 9.3, 7.4, 2.0 Hz), 7.84 (2H, dm, J 8.4 Hz), 7.66 (1H, tt, J 7.4, 1.3 Hz), 7.52 (2H, tm, J 7.8 Hz), 7.38 (1H, ddd, J 6.8, 4.9, 1.9 Hz). LCMS (ES+) RT 3.27 minutes, 202 (M+H)+
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(N)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 114 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (150 mg, 0.250 mmol) was dissolved in dimethoxyethane (10.5 mL), and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (110 mg, 0.500 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg, 0.030 mmol), potassium carbonate (173 mg, 1.25 mmol) and water (0.090 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-aminophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (76.5 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:25])[C:13]([F:24])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1.CCN(CC)CC>ClCCCl>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[C:13]([F:24])[C:12]([F:25])=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1
Reactant: Fc1cc2nn(-c3ccc(Cl)cc3)c(NC3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)N(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-amine was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 4 d under reflux conditions to give the title compound as light brown gum. MS: m/e=573.0 [M+H+].
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:9]([CH2:12][CH3:13])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.S(=O)(O)[O-].[Na+].[C-:32]#[N:33].[K+]>O>[CH2:14]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:12][CH3:13])[C@H:10]([OH:11])[C:32]#[N:33])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H]([C@H](O)C#N)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, (S)-2-(dibenzylamino)butanal (8.55 g, 32.0 mmol, Eq: 1.00) was combined with dioxane (70 ml) to give a light yellow solution. The reaction was stirred for 10 min at 0° C. Then sodium bisulfite in water (40%, 26.5 ml) was added. The reaction was stirred for another 10 min at 0° C. Then potassium cyanide (8.33 g, 128 mmol, Eq: 4), diluted in water (35 ml) was added. The reaction was stirred overnight at RT. The reaction mixture was poured into water (75 ml) and extracted with ethyl acetate (2×75 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% ethyl acetate in heptane). The title compound was obtained as a light yellow oil (6.49 g, 68.9%, MS (m/e)=295.3 [M+H+]).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)(=[O:20])=[O:19])[CH2:9][CH2:8]1.O.NN>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
0.06 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2nitrobenzenesulphonamide is dissolved in 500 ml of MeOH, 2.4 g of 5% Pd-C are added, the mixture is heated to boiling and 0.17 mol of hydrazine hydrate in 50 ml of MeOH is added dropwise within 15 minutes. After boiling for a further 30 minutes, the mixture is filtered, the filtrate is evaporated, the residue is taken up in diethyl ether, washed with water, evaporated again and crystallised from isorpopanol-isopropyl ether.