Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54](=O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[BH3-]C#N.[Na+]>CCO.C1COCC1>[CH2:54]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:5]2=[O:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(NCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To 100 mg (0.14 mmol) of the amine from Example 40 in 2 mL of EtOH was added 16 mg (0.15 mmol) of benzaldehyde. The reaction mixture was heated to 60° C. for 1 hour, cooled to 0° C. and treated with 0.29 mL (0.29 mmol) of a 1M solution of NaCNBH3 in THF. The reaction mixture was stirred overnight, concentrated in vacuo, and the residue partitioned between 25 mL of EtOAc and 15 mL of water. The phases were separated and the organic phase was washed with brine (1×25 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 25% EtOAc/hexanes to give 45 mg (0.06 mmol) of a yellow foam. 1H-NMR (CDCl3 300 MHz): 0.88 (t, 3H, J=7.4 Hz), 1.31 (m, 2H), 1.66 (m, 2H), 2.61 (3 line m, 2H, J=7.8 Hz), 4.32 (bs, 1H), 4.43 (bs, 2H), 5.28 (bs, 2H), 6.88 (m, 8H), 7.08 (m, 3H), 7.20-7.53 (m, 19H), 7.91 (d, 1H).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[S:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1>C1COCC1>[F:29][C:18]1[CH:17]=[C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][NH:8][C:6]([NH2:5])=[O:7])[O:14][C:13]2=[O:15])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: NC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Trimethylsilyl isocyanate (0.138 ml, 1.02 mmol) is added to a mixture of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4] thiadiazin-5-one (0.30 g, 0.925 mmol) in THF (10 ml). The mixture is stirred at room temperature overnight and then is evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.22 g, 65%); 1HNMR (300 MHz, DMSO-d6) δ 3.29-3.36 (m, 2H), 3.59 (s, 2H), 3.78 (dd, J=6.3, 9.1 Hz, 1H), 4.13 (t, J=9.1 Hz, 1H), 4.69-4.77 (m, 1H), 5.58 (s, 1H), 6.31 (t, J=6.0 Hz, 1H), 7.42 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=2.2, 14 Hz, 1H), 7.68 (t, J=8.8 Hz, 1H), 11.6 (s, 1H); mp 235-6; MS (m/z): [M+H]+=368.
Reaction SMILES: [H-].[Na+].[Si]([O:20][CH2:21][CH2:22][OH:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[CH:32][N:33]=2)[N:30]=1>CN(C)C=O>[N:33]1[CH:32]=[N:31][N:29]2[C:28]=1[CH:27]=[CH:26][C:25]([O:20][CH2:21][CH2:22][OH:23])=[N:30]2
Reactant: Clc1ccc2ncnn2n1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
60% Oily sodium hydride (510 mg) was suspended in N,N-dimethylformamide (70 ml), followed by addition of 2-(t-butyldiphenylsilyloxy)ethanol (3.83 g). The mixture was stirred at room temperature for 1 hour, followed by addition of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (1.98 g). The mixture was stirred at room temperature for 5 hours and poured into ice-water, followed by extraction with ethyl ether. The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 ml), followed by addition of tetra-n-butylammoniumfluoride trihydrate (2.02 g). The mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the objective compound were collected and concentrated to yield the title compound (0.875 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:6][CH:5]=1)N.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][CH2:29][CH:30]=O.C(OCC)(=O)C>C(O)(=O)C>[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=2)[NH:2][CH:30]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: CN(C)C(=O)Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of 2-(4-hydrazinophenyl)-N,N-dimethylacetamide hydrochloride (0.875 g, contains 0.00315 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal, diethyl acetal (0.873 g) was heated under reflux in 25% aqueous acetic acid (100 ml) for 30 min. The mixture was poured into ethyl acetate (150 ml) and the aqueous phase was separated. This was washed with ethyl acetate (150 ml) and the organic extracts were combined. The yellow solution was washed successively with water (150 ml) 8% sodium bicarbonate solution (150 ml) and finally water (150 ml). Evaporation of the dried (Na2SO4) solvent gave a yellow solid which crystallised from propan-2-ol to give the title compound as a pale yellow powder (0.91 g) m.p. 193°-4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2c1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C., for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(c2cccc(Br)c2)CCOCC1
Yield: 79.1 %

Procedure:
A stirred mixture of ethyl 4-(3-bromophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (36.5 g, 117 mmol), an aqueous solution of lithium hydroxide (6.14 g, 146 mmol, 50 ml), methanol (150 ml) and THF (150 ml) was refluxed for 1 day. The reaction mixture was partitioned between ether (100 ml) and 10% aqueous potassium hydroxide solution (300 ml). The ethereal layer was separated, extracted with 10% aqueous potassium hydroxide solution (2×100 ml) and discarded. The combined aqueous extracts were acidified with concentrated hydrogen chloride and the resulting white precipitates were collected by filtration, washed with water and dried to constant weight under vacuum at 80° C. to give the titled compound as white solids (26.4 g, 79%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1NCC(C)C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylideneamine (1.15 g, 3.88 mmol) in 15 mL of methanol was treated with NaBH4 (0.44 g, 11.6 mmol) and stirred under an atmosphere of nitrogen. After 18 h, the reaction was concentrated under reduced pressure. The residue was partitioned between CHCl3 and water, and the phases were separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange oil. Chromatography (SiO2, 97:3 CHCl3:MeOH), gave N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylamine (0.69 g) as clear, colorless crystals.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([CH:26]=O)[C:21](OCC)=[O:22])[CH:15]=[N:16][C:17]=1[CH3:18]>CO>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[C:21](=[O:22])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][CH:26]=2)[CH:15]=[N:16][C:17]=1[CH3:18]
Reactant: CCOC(=O)C(C=O)Cc1cnc(C)c(C)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C

Procedure:
Nitroguanidine (6.05 g) was added to a solution of sodium methoxide (prepared from 1.45 g sodium) in dry methanol (65 ml) and the mixture was heated under reflux for 0.75 hours. Ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate (14.3 g) was added and the mixture was heated under reflux for 40 hours and evaporated to dryness. Water (40 ml) was added to the residue and the mixture was extracted with chloroform. The aqueous phase was adjusted to pH 6 with hydrochloric acid and the solid which separated was filtered off and recrystallised from dimethylformamideethanol to give 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone, m.p. 212°-3°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:18]1[N:23]=[C:22](C=O)[CH:21]=[CH:20][CH:19]=1.[CH:26]([C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:30]=1[NH2:31])([CH3:28])[CH3:27]>C(O)=O.CO>[OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:4][C:3]=1[C:18]1[NH:23][C:22](=[N:31][C:30]2[C:32]([CH:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=[CH:35][C:29]=2[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1cc(-c2ccccc2)c(O)c(-c2cccc(C=O)n2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O=CO
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(-c2cc(C(C)(C)C)cc(-c3ccccc3)c2O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 6-(2′-hydroxy-3′-phenyl-5′-tert-butylphenyl)-2-formyl-pyridine (12) (3.17 g, 9.17 mmol) in the minimum volume of methanol was added 2,6-diisopropylaniline (1.79 g, 10.1 mmol). After the addition of a few drops of formic acid, the solution was stirred overnight. The cloudy yellow reaction mixture was then filtered through a frit, and the solid washed with methanol (3×5 mL), giving compound 13 as a yellow solid. Yield: 2.92 g (65%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[Na+].[CH3:10][N:11]([C:13]([N:16]([CH3:18])[CH3:17])(Cl)[Cl:14])[CH3:12].C(OCC)C>C(#N)C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:10][N:11]([C+:13]([N:16]([CH3:18])[CH3:17])[Cl:14])[CH3:12]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)[C+](Cl)N(C)C
Reaction time: 1 h

Procedure:
2.01 g (11.7 mmol) of sodium trifluoromethanesulfonate in 20 ml of acetonitrile are added with stirring at room temperature to a solution of 2.0 g (11.7 mmol) of bis(dimethylamino)dichloromethane in 20 ml of acetonitrile. The mixture is stirred for one hour, and 40 ml of diethyl ether are added. After stirring for 12 hours, the solid NaCl is subsequently filtered off. The solvent is distilled off, and the crystals formed are dried under a reduced pressure of 10.0 Pa, giving 3.29 g of bis(dimethylamino)chlorocarbenium trifluoromethanesulfonate, corresponding to a yield of 98.8%.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:18]=[N:19][N:20](C5CCCCO5)[CH:21]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[N:9]2[C@@H](C2C=CC(OC)=CC=2)C)=[N:4][CH:5]=[N:6][CH:7]=1>FC(F)(F)C(O)=O.CO>[F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][NH:19][CH:18]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[NH:9]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncncc2F)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ncncc2F)NC(=O)c2cc(-c3cn[nH]c3)ccc21
Temperature: 77.5 °C

Procedure:
Dissolve 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (65 g, 123 mmol) in trifluoroacetic acid (600 mL) and heat to 75-80° C. for 16 hours. Evaporate under reduced pressure and dilute with ethyl acetate (500 mL) and water (500 mL). Adjust the pH of the aqueous layer to 8-9 with aqueous 6 N NaOH, extract the aqueous layer with ethyl acetate (3×500 mL), combine the organic layers, wash with saturated aqueous sodium chloride, dry with sodium sulfate, filter, and evaporate under reduced pressure. Chromatograph the crude product on silica gel with 50-100% ethyl acetate/petroleum ether. Combine the product fractions and evaporate under reduced pressure to give a yellow foam (33 g, 87% crude). Repeat the reaction conditions with 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one and combine the products (10 g, 18.9 mmol). Dissolve the combined products in methanol and stir with SiliaBond® Thiol (Silia MetS® Thiol) at 15-20° C. for 20 hours, filter, and evaporate under reduced pressure to give the title compound with 77% ee (38 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[N:23]1C=CC=CC=1.ClC(OC(C)C)=O.N>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([C:7](=[O:8])[NH2:23])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)O)cc1
Reactant: c1ccncc1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(N)=O)cc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
5-Chloro-N-methyl-N-(p-toluenesulfonyl)anthranilic acid (5.00 g (14.7 mmol)) and pyridine (1.33 ml (16.4 mmol)) were dissolved in 70.0 ml of acetonitrile. To this, under cooling with ice and with stirring, isopropyl chloroformate (2.00 g (16.3 mmol)) was added dropwise. After 30 minutes' stirring under ice-cooling, ammonia gas (ca. 1.25 g (73.4 mmol)) was bubbled into the reaction mixture. The resulting mixture was stirred under cooling with ice for 30 minutes and at room temperature for 20 hours, and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dilute sodium hydroxide solution and water, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give crude crystals. Diethyl ether was added to these crystals, followed by filtration and washing, to give 1.70 g (34%) of the title compound.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=C(Cl)Cc1ccc(OC2CCCCC2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclohexyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Manufacturing Example 79-1-4 and 3-ethynyl-pyridine-2,6-diamine (47.6 mg, 0.357 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (195 μL, 1.4 mmol). This reaction mixture was stirred for 4 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (83 mg, 41%).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([O:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cl:16]Cl.O>C(O)(=O)C>[Cl:16][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[O:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: O=c1ccc2nc3ccccc3oc-2c1
Reactant: ClCl
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3oc-2c1Cl

Procedure:
To a solution of 1.2 g of 3H-phenoxazin-3-one in acetic acid (25 ml) was added K2Cr2O7 (3.7 g). A solution of chlorine in acetic acid was added dropwise to the resulting suspension. After disappearance of the starting material, as monitored by TLC, the reaction mixture was poured into 200 ml of H2O and the resulting precipitate was filtered (1.2 g) and chromatographed on silica gel to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[C@@H:12]1[C@:17]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[C@H:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH2:15][C:14](=[O:35])[NH:13]1)[CH:2]=[CH2:3].[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39].[C:44]([O:48][C:49](=[O:52])[CH2:50]Br)([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH:12]1[C:17]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH2:15][C:14](=[O:35])[N:13]1[CH2:50][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:52])[CH:2]=[CH2:3].[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCOc1ccc(I)cc1[C@H]1NC(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(I)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 49 %

Procedure:
In a manner similar to the method described in example 1e, racemic (2′R, 3R,4′S)-2′-(2-allyloxy-5-iodo-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (5 g, 6.6 mmol) prepared in example 18c was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethyl-formamide to give racemic (2′R, 3R, 4′S)-2′-(2-allyloxy-5-iodo-phenyl)-1′-[(tert-butoxycarbonyl)methyl]-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield: 2.8 g, 49%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C.CC(OC)(C)C>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:29][CH2:28]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Solvent: COC(C)(C)C
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4O)CC3)c(=O)oc2c1
Yield: 22 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-hydroxyphenyl)piperazine; yield 22%; m.p. 164°-165° C. (from ethanol/TBME).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O[N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:50]=[C:49]([N:51]3[CH2:56][CH2:55][CH:54]([OH:57])[CH2:53][CH2:52]3)[CH:48]=[CH:47][C:27]=2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:29])[CH2:21][C:20]1=C=O)(C)(C)C.FC1C=CC(C(NC2C=CC=CC=2C(NC2C=CC(Cl)=CN=2)=O)=O)=C(OC2CCN([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])CC2)C=1.OC1CCNCC1>>[C:96]([O:95][C:93]([N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:26]2[CH:50]=[C:49]([N:51]3[CH2:52][CH2:53][CH:54]([OH:57])[CH2:55][CH2:56]3)[CH:48]=[CH:47][C:27]=2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:29])[CH2:23][CH2:24]1)=[O:94])([CH3:99])([CH3:98])[CH3:97]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CC(C)(C)ON1CCC(Oc2cc(N3CCC(O)CC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1=C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OC1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCC(O)CC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(4-hydroxypiperidin-1-yl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (196 mg, 0.30 mmol, 39%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 4-hydroxypiperidine.