Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:18]/[C:19](/[CH3:25])=[CH:20]\[C:21]([O:23][CH3:24])=[O:22]>C(O)(C)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([CH3:25])[NH:18][C:13]([CH3:15])=[C:12]1[C:11]([OH:17])=[O:16]
Reactant: CC(=O)CC(=O)O
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (0.70 g), 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of acetoacetic acid (1.42 g) and methyl 3-amino-crotonate (0.46 g) in tert-butyl alcohol (3 ml) was refluxed for 4.5 hours. The resulting mixture was cooled to 25° C. and then concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (60 g) and eluted with a mixture of chloroform and methanol (100:1 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure. The residue obtained was recrystallized from a mixture of diethyl ether and diisopropyl ether to give 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 4-(2,3-dichlorophenyl)-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid (1.11 g), mp 115° to 117.5° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3F)C=CC2=O)CC1)(C)(C)C>>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (500 mg, 2.8 mmol) was deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.3 mmol) as described for Intermediate 20. Colorless solid, 637 mg (57%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C)C=O>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][C:38](=[O:39])[NH:37][CH2:35][CH3:36])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Oc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (540 mg), triethylamine (0.51 mL) and ethyl isocyanate (0.29 mL) was stirred in dry N,N-dimethylformamide (3 mL). The product slowly precipitated from the reaction mixture and was collected by filtration and washed with ether to yield the title compound as a yellow solid (210 mg).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccccc1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent (equivalent relative to a carbonyl compound as a starting raw material; the same, hereinafter)) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.06 g (10 mmol) of benzaldehyde in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:33][CH2:34][CH2:35][NH:36][C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chloro-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 54.9 mg (0.28 mmol) of 6-[(2-aminoethyl)amino]-pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 2.33 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 113 mg (77% of theory) of the product as a solid.
Reaction SMILES: CS([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)(=O)=O.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:38]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:6]=1)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
4'-Methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol) and hexadecyl alcohol (2,42 g, 0.010 mol) were added to N,N-dimethylformamide (0.1 liter). At 15° C., sodium hydride (60% content, oil dispersion, 0.8 g) was added thereto over a period of about 10 minutes. The entire solution was stirred for 30 minutes and then the reaction mixture was reacted under reflux for 4 hours. After cooling to room temperature, the reaction mixture was poured into an aqueous 4M sodium chloride solution (0.3 liter). The crystal that precipitated was taken out by filtration under suction and then washed with water and hexane. The crystal was again dissolved in chloroform and washed with 1M hydrochloric acid and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The resulting crystal was recrystallized from hexane to obtain 4.36 g of the above-entitled product (T-6). Yield: 92%. m.p. 97.5 to 99.0° C.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:44])[C:38]=2[CH:37]=[N:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:28]([N:35]1[C:43]2[C:38](=[C:39]([NH:44][C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[CH:10][C:11]4=[N:17][CH:16]=3)=[O:20])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(OCC(O)CO)ccn12
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A DCM solution of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Example 58, Steps A-C, 109.7 mg, 0.375 mmol) was treated at ambient temperature with oxalyl chloride (1.1 equivalents) and a drop of DMF. After gas evolution ceased, 1-benzyl-1H-indazol-4-amine (83.8 mg, 0.375 mmol) and Hunig's base (1.2 equivalents) were added, and stirring continued overnight. The resulting mixture was concentrated, and triturated with diethyl ether, followed by chromatographic purification on silica with 10% MeOH/DCM as eluent to provide 25.2 mg of the desired product. MS (ES+APCI) m/z=458 (M+H) detected.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[O:8][C:9]2[C:17]([CH2:18][CH:19]=[CH2:20])=[CH:16][CH:15]=[C:14]([O:21][CH2:22][CH:23]3[O:27][CH2:26][CH2:25][CH2:24]3)[C:10]=2[C:11](=[O:13])[CH:12]=1)=O)C>C(O)C>[CH2:18]([C:17]1[C:9]2[O:8][C:7]([C:5]([NH2:1])=[O:4])=[CH:12][C:11](=[O:13])[C:10]=2[C:14]([O:21][CH2:22][CH:23]2[O:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCc1ccc(OCC2CCCO2)c2c(=O)cc(C(=O)OCC)oc12
Reactant: N
Solvent: CCO
Product: C=CCc1ccc(OCC2CCCO2)c2c(=O)cc(C(N)=O)oc12
Temperature: 0 °C

Procedure:
Anhydrous ammonia gas was passed through a stirred solution of 38.4 parts of 8-allyl-5-tetrahydrofurfuryloxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in 600 parts of anhydrous ethanol at 45° C for 3 hours. The resulting dark, reddish brown solution was cooled to 0° C. A white crystalline solid was formed, which was collected and dried in vacuo. 24.7 Parts of 8-allyl-5-tetrahydrofurfuryloxy-4-oxo-4H-1-benzopyran-2-carboxamide were obtained, melting point 211.5°-213.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([N:16]=[C:17]=[O:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]>C(OCC)C>[C:11]([NH:16][C:17]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: C=C(C)C(=O)NC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 79 %

Procedure:
Into 500 ml of a diethyl ether solution of 13.8 g (0.1 mol) of p-nitroaniline was added dropwise 50 ml of a diethyl ether solution of 11.1 g (0.1 mol) of methacryloyl isocyanate over about 30 minutes in an ice bath. After completion of the addition, the produced crystal was filtered and the filtrate was distilled under a reduced pressure. The yellow solid gathered from the filtration and the distillation residue was recrystallized with methyl ethyl ketone to obtain 19.7 g of 1-methacryloyl-3-(4-nitrophenyl)urea (Compound 1) which had a decomposing point of 241° to 244° C. and was yellow needle crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH2:31][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][N:24]=2)=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A solution of N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (400 mg, 0.905 mmol, prepared as described in Method 15) in dichloromethane (5 ml) was added over 20 min to a stirred mixture of piperidine (0.1 ml, 1.00 mmol) sodium triacetoxyborohydride (212 mg, 1.0 mmol), powdered 3A molecular sieve (500 mg) and dichloromethane (15 ml) at −20° C. under nitrogen. The reaction mixture was stirred for 16 hours at ambient temperature before being filtered and washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica eluting with ethyl acetate to afford the title compound as a cream solid (252 mg, 55%); NMR Spectrum: (DMSO-d6) 1.40 (m, 2H), 1.45 (s, 9H), 1.46 (m, 4H), 2.39 (m 4H), 3.58 (s, 2H), 7.17 (m, 2H), 7.56 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.31 (d, 1H), 8.69 (s, 1H), 8.87 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+512.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][Zn+].Br[C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+]>C1COCC1>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Reactant: [Zn+]CCC1OCCO1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1CCC1OCCO1
Yield: 52.2 %

Procedure:
A THF solution of (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (35 mL. 17.3 mmol) was added to a degassed solution of ethyl 5-bromo-2-phenylthiazole-4-carboxylate (3.6 g, 11.5 mmol) and tetrakistriphenylphosphine palladium (666 mg, 0.58 mmol) in THF (20 mL). The reaction mixture was heated at reflux for 16 h then poured into sat aq NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-100% gradient) to give ethyl 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenylthiazole-4-carboxylate (2.0 g, 52% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O>CO>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccccc2OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(COc2ccccc2OCc2c[nH]cn2)cc1
Temperature: 70 °C
Yield: 60.3 %

Procedure:
A solution of 4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (34 mg) in MeOH (2 ml) was treated with AcOH (0.1 ml) and was heated to 70° C. for 5 hours. The mixture was concentrated. The crude product was purified by column chromatography to give 4-(2-benzyloxy-phenoxymethyl)-1H-imidazole (11 mg) as a colorless amorphous solid. MS (ISP): 281.4 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH:27][CH2:28][CH2:29][NH2:30]>>[OH:27][CH2:28][CH2:29][NH:30][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][S:23](=[O:26])[CH2:24][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: CN(c1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CN(c1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(N-methyl-anilino)-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 237°-239° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: ClC[CH2:3][CH2:4][C:5]#[N:6].[N:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]N[CH2:9][CH2:8]1.C(N(CC)CC)C.CCOCC>C1(C)C=CC=CC=1>[CH2:4]1[CH:5]([N:6]2[CH2:11][CH2:12][N:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: N#CCCCCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2CC2)CC1
Temperature: 20 °C
Yield: 101 %

Procedure:
124 g (1.2 M) of 4-chlorobutyronitrile were dissolved in 600 ml of toluene and the mixture was refluxed under a Dean-Stark separator for 1 hour. The resultant solution was cooled and then 158 g (1 M) of ethyl piperazine-1-carboxylate and 170 ml (1.2 M) of triethylamine were added thereto and the mixture was refluxed for 24 hours. The resulting suspension was cooled to 20° C. and one liter of ether was added thereto. The precipitate of triethylamine hydrochloride was filtered off and the filtrate was decolorized with charcoal and evaporated to dryness to obtain 200 g of ethyl 4-(3-cyclopropyl)-piperazine-1-carboxylate in the form of a brown oil which was distilled under reduced pressure at a boiling point of 140°-150° C. at 0.05 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O-:11])([O-])=O.[K+].[K+].[CH3:14][N:15]1CCN[CH2:17][CH2:16]1>CN(C=O)C>[O:11]1[CH2:8][CH2:14][N:15]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of ethyl 2-chloroacetate (0.5 g, 5.74 mmol) in DMF (70 ml) at 10° C. were added K2CO3 (1.98 g, 14.34 mmol, 2.5 eq.) and 1-methylpiperazine (1.05 g, 8.6 mmol, 1.5 eq.) and the mixture was stirred at RT for 2 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to afford the product in 74% yield (0.74 g). LC-MS (ESI): Calculated mass: 173.2, Observed mass: 174.0 [M+H]+ (rt: 0.20 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Mg].BrCCBr>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:14])[CH2:33][C@H:34]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]([CH3:45])[CH3:46])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](CCl)COCc1ccccc1
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Alternatively, A solution of 27 g of aldehyde 7 in 30 mL of tetrahydrofuran is added to a room-temperature solution of the Grignard reagent prepared by refluxing 20 g of ((S)-2-chloromethyl-3-methyl-butoxymethyl)-benzene with 3.2 g of magnesium in 120 mL of tetrahydrofuran containing 1.3 g of 1,2-dibromoethane for 4 h. The reaction is stirred for 1 h at room temperature, then 100 mL of 2 N sulfuric add is added. The mixture is stirred until the excess magnesium has dissolved, then the phases are separated and the organic phase washed with 50 mL of 12% sodium chloride solution. The organic phase is concentrated in vacuum to give e.g. 42.6 g of the crude alcohol 8 as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.C(N1C2C(=CC([F:80])=CC=2)CC1=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:80])=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Product: O=C1N(Cc2ccccc2)c2ccc(F)cc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Yield: 63 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (501.4 mg, 1.181 mmol) and 1-benzyl-5-fluoroindolin-2-one (285.0 mg, 1.181 mmol). Purification using Biotage Isolera (SNAP 25 g column, 25-100% EtOAc in hexane) yielded the title compound as a cream solid (352 mg, 63%; 97% ee) with the major (1R,2S) enantiomer eluting at 7.03 min (Phenomenex Lux 5μ Cellulose-1 (150×4.6 mm), 1.0 mL/min isocratic at 80% EtOH in hexane for 1.0 min, then gradient 80-90% EtOH in hexane over 10 min). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 5.95 min using this method. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.40-7.27 (m, 8H), 7.17 (s, 1H), 7.11 (d, J=7.2 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 6.67-6.62 (m, 2H), 5.62 (d, J=15.6 Hz, 1H), 5.55 (d, J=15.6 Hz, 1H), 5.51 (t, J=6.0 Hz, 1H), 5.10 (d, J=15.6 Hz, 1H), 4.94 (d, J=16.0 Hz, 1H), 3.53 (t, J=8.4 Hz, 1H), 2.32 (dd, J=9.2, 4.4 Hz, 1H), 2.02 (dd, J=8.0, 3.2 Hz, 1H), MS ESI 474.3 [M+H]+, calcd for [C31H24FN3O+H]+ 474.2.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5].[N-:9]=[N+:10]=[N-:11].[Na+].CN(C)C=O>CCOCC>[N:9]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[S:5])=[N+:10]=[N-:11]
Reactant: CCOC(=S)CCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=S)CCN=[N+]=[N-]

Procedure:
After stirring a mixture of 6.7 g. of ethyl chloromethylthioacetate, 5 g. of sodium azide and 15 ml. of dimethylformamide for 17 hours at 45° C., the reaction mixture was diluted with 150 ml. of ether, followed by washing with water for three times. By drying the ether layer over magnesium sulfate and then distilling it under reduced pressure, 6.1 g. of ethyl azidomethylthioacetate was obtained as a liquid having a boiling point of 77° - 80° C. (3 mm Hg.).