Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[O:3]1.[OH-].[Na+].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18].[Cl-]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])[CH2:5][CH:4]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[O:3]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C=CCOCC1CNC(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C=CCOCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
To a reaction mixture of 25 percent w/v, 34.2 milliliters of 2,2-dimethyl-5-allyloxymethyl oxazolidine solution in 100 milliliters benzene with 4 grams of 50% sodium hydroxide solution, was added dropwise, 7.4 grams of dichloroacetyl chloride. Cooling in an ice bath and vigorous stirring was maintained during the addition of the chloride. Upon completion of the reaction the mixture was washed with water, dried, separated and the organic solvent removed in vacuo. There was obtained 10.0 grams of the title compound, nD30 1.4705. Analytical data supports the structure.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)(=O)C>[CH2:13]([N:29]1[C:30]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:31][CH:32]=[C:33]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCCCn1cccc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCn1c(C2=CC(=O)c3ccccc3C2=O)ccc1C1=CC(=O)c2ccccc2C1=O
Yield: 38 %

Procedure:
The same procedure as in Example 7 was followed by stirring 10 millimol of 1,4-naphthoquinone with 2.5 millimol of N-hexadecylpyrrole in 40 ml of acetic acid at 50° C. for 5 hours. The 1-hexadecyl-2,5-bis(1,4-naphthoquinon-2-yl)pyrrole was thus obtained in a yield of 38% after chromatography on a column of silica.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:23])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[O:17])=[CH:11][CH:10]=1.O=O>CCOCC>[C:20]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:21])[CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:23])=[CH:14][CH:13]=1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(OC(=O)CCC(=O)Cl)cc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCC(=O)OOC(C)(C)C)cc1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a vigorously stirred solution of 15.6 g. (0.143 mole) of 82.0% t-butyl hydroperoxide and 57.0 g. (0.143 mole) of aqueous 10% sodium hydroxide at 5°-10° C. was added slowly 24.6 g. (0.109 mole) of 3-(p-tolyloxycarbonyl)propionyl chloride (prepared from p-tolyl 3-carboxypropionate and thionyl chloride) in 50 ml. of diethyl ether. The reaction mixture was then stirred at 5°-10° C. for three hours, after which additional ether was added to the mixture and the resulting ether solution was washed, first with 10% sodium hydroxide solution, and finally with water until the solution was neutral. After drying over anhydrous MgSO4 and removal of the ether in vacuo 28.2 g. (theory, 30.4 g.) of white solid, m.p. 72°-77° C., was obtained. The assay according to "active oxygen" content was 100% and the corrected yield was 92.8%.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11].[I-].[Na+].O[CH2:23][CH:24]([CH2:26]O)O>O>[CH3:19][S:16]([C:15]1[C:7]2[N:6]=[CH:26][CH:24]=[CH:23][C:8]=2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1N
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c2cccnc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
38 ml of water and 102 g of concentrated sulfuric acid were heated to 110° C. At 95° C., 0.25 mol of 3-amino-4-methylsulfonylbenzoic acid was added. The mixture was then heated to 140° C., and 0.8 g of sodium iodide and 0.3 mol of glycerol were added. The reaction temperature was then increased to 150° C. While the mixture was heated to and stirred at 150° C. (1 hour), 47 g of distillate were collected. After cooling, the reaction mixture was carefully admixed with 200 ml of water and diluted with a further 800 ml of water. Using 20% strength aqueous sodium hydroxide solution, the pH was adjusted to 13 and the mixture was filtered and adjusted to pH 3.5 with sulfuric acid. This procedure was repeated. A precipitate was formed which was filtered off with suction. The filtrate was adjusted to pH=2 and the resulting precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH3:19])[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:3]1.[Br:28]Br>C(Cl)Cl>[Br:28][C:9]1[CH:10]=[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@H:6]([C:7]=3[CH:8]=1)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:3][N:2]4[CH3:1])=[C:13]([S:18][CH3:19])[NH:12]2
Reactant: BrBr
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(SC)c(c34)C[C@H]2N(C)C1
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4[nH]c(SC)c(c34)C[C@H]2N(C)C1
Reaction time: 0.33 h

Procedure:
A solution is prepared from 11.2 g of 3-(6-methyl-2-methylthio-8α-ergolinyl)-1,1-diethylurea (29 mmol) in 400 ml of methylene chloride p.a. and, at room temperature, 1.45 ml of bromine (26 mmol) dissolved in 100 ml of methylene chloride p.a. is added dropwise thereto within 20 minutes. After 15 minutes of agitation, the solvent is distilled off under vacuum, the residue is taken up in methylene chloride and methanol, and crystallized by adding ethyl acetate with a small amount of diisopropyl ether and by removing the readily volatile solvents by distillation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:17]([O:24][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl alcohol and DBU in dioxane. ES-MS m/e (%): 304 (M{37Cl}+H+, 30), 302 (M{35Cl}+H+, 100).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chloroacetyl chloride (0.483 mL) was added dropwise over 10 minutes to a vigorously stirred mixture at 0° C. of tert-butyl 4-(2-aminoethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step b) (1.1 g) in ethyl acetate (25 mL) and potassium carbonate (1.77 g) dissolved in water (20 mL). The mixture was then stirred at 0° C. for 45 minutes before being extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.9 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=O)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH2:40].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH:40][CH2:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:28])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc(-c3c(C)noc3C)c3c4c2[nH]c(=O)n4[C@@H](c2ccccn2)CO3)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
A solution (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (250 mg, 0.664 mmol) in ethanol (12.5 mL) was treated with 1-(2,4-dimethoxyphenyl)methanamine [Aldrich #: 432725](150 μL, 0.996 mmol) and acetic acid (20.0 μL, 0.352 mmol) and heated at 60° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (210 mg, 3.3 mmol) and stirred at room temperature for 3 h. The reaction mixture was then quenched with acetic acid (1 mL) and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the desired product (0.40 g, 97%) as a single enantiomer which was used without further purification. LCMS calculated for C29H30N5O5 (M+H)+: m/z=528.2. found: 528.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](=[O:13])C>C1COCC1.CCCCC>[CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH2:11][OH:13])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cccs1
Reactant: CC=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCNC(=O)c1sccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 500 %

Procedure:
A solution of thiophene-2-carboxylic acid ethylamide (465 mg, 3 mmol) in dry THF (12 mL) is cooled to −78° C. under an argon atmosphere. Tert-BuLi (5.3 mL of a 1.7 M solution in pentane, 9.0 mmol) is added dropwise at −78° C. and the reaction mixture is stirred for 3 h. The reaction mixture is treated with neat acetaldehyde (3 mL, 53 mmol) and is stirred at −78° C. for 2 h and then warmed to room temperature overnight. The reaction mixture is quenched by the addition of water (35 mL). The reaction mixture is transferred to a separatory funnel and the organic phase is collected. The aqueous layer is extracted 5 times with Dichloromethane. The combined organic extracts are washed with water, and saturated aqueous NaCl, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, 25% EtOAc/hexane) to give the title compound (298 mg, 15 mmol) in 50% yield.
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[N:11]1([C:2]([CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: CCOC(=O)CC(=O)CC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(CC)N1CCCC1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Ethyl 3-oxopentanoate (2.5 mL, 17.6 mmole) and pyrrolidine (1.4 mL, 17.1 mmole) were dissolved in benzene and added to a 100 mL flask fitted with a Dean-Stark water separator. The reaction was stirred at reflux for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the product was dried in vacuo, affording ethyl 3-(pyrrolidin-1-yl)pent-2-enoate (3.4 g, 98% yield). The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[C:42]([O:56][CH3:57])=[N:43][CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][CH:35]=3)(=[O:39])=[O:38])[C:42]([O:56][CH3:57])=[N:43][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2OC)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cnc2OC)cc1
Yield: 54.5 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 4-methoxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (149 mg, 0.34 mmol), sodium carbonate (2M, 511 μl, 1.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol) according to the method described in Example 3 to give 82 mg (55% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Yield: 57.2 %

Procedure:
A solution of 17β-cyclopropyloxy-androst-5-en-3β-ol (19.36 g, 58.9 mM) in acetone (1.9 L) is cooled to -3° C and then treated with Jones reagent (20 ml). The excess reagent is decomposed with methanol. The solids are removed by filtration. The filtrate is concentrated to a green oil which is purified by flash chromatography on silica gel to give 17β-cyclopropyloxy-androst-4-en-3-one (11.0 g, 57%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: NCC(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(NCC(N)=O)cc1OCC2
Temperature: 85 °C
Yield: 8 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and glycinamide hydrochloride salt in NMP were heated at 85° C. for 20 h. The reaction mixture was cooled and loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol and appropriate fractions concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% 2M ammonia in methanol in DCM). The solid was recrystallised from methanol to give 404 as a white solid (19 mg, 8%). LCMS: RT=2.14 min, [M+H]+=369. 1H NMR 400 MHz (DMSO-d6) δ: 9.01 (1H, s), 7.90 (1H, d, J=0.63 Hz), 7.82 (1H, s), 7.32 (1H, br, s), 7.01 (1H, br, s), 6.11 (1H, s), 5.97-5.88 (1H, m), 4.49-4.48 (4H, m), 3.84 (2H, d, J=4.26 Hz), 1.48 (6H, d, J=6.60 Hz)
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:28][O:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:8][C:7]=2[N:6]=1>C(O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:28][O:29][NH2:30])[N:17]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1c(CON)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Hydrazine hydrate (0.753 mL, 15.5 mmol) was added to a stirred suspension of tert-butyl 2-(4-amino-7-(benzyloxy)-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (3.15 g, 5.18 mmol) in ethanol (50 mL). The suspension was stirred at room temperature for 3 hours, then was filtered. The filtrate was concentrated under reduced pressure to yield 2.43 g of crude tert-butyl 2-[4-amino-2-[(aminooxy)methyl]-7-(benzyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate that was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:29])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][C:25]([CH3:27])=[N:24][C:23]=3[Cl:28])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:30]([B-](F)(F)F)=[CH2:31].[K+]>C(O)CC.CCOC(C)=O>[Cl:28][C:23]1[N:24]=[C:25]([CH3:27])[NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([CH:30]=[CH2:31])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:29])=[O:21]
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Br)cc(C#N)c3)c2F)[nH]1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)c1
Temperature: 100 °C
Yield: 61.3 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (0.480 g, 0.964 mmol), potassium vinyltrifluoroborate (0.194 g, 1.445 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.079 g, 0.096 mmol) in n-propanol (8 ml) was added TEA (0.672 ml, 4.82 mmol) and the reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazol e-5-carboxamide (0.263 g, 0.591 mmol, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (t, 1H), 7.77 (s, 1H), 7.47 (d, 1H), 7.40 (br. s., 1H), 7.32 (t, 1H), 7.26 (br. s., 1H), 6.72 (dd, 1H), 6.01 (d, 1H), 5.41 (d, 1H), 4.51 (d, 2H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[O:16]([C:18]#[N:19])[Na].FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][C:18](=[O:16])[NH2:19])[CH2:5][O:4]1
Reactant: N#CO[Na]
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 15 grams of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (0.0625 mols), 8.12 grams NaOCN (0.125 mols), and 75 ml methylene dichloride is stirred at 25°-35° C. while 14.3 grams trifluoroacetic acid is added dropwise. The mixture is stirred for 16 hours at 40° C. The product is filtered and the filter cake washed with methylene dichloride. The filtrate is washed with water and dried over Na2SO4 prior to vacuum-stripping. The reaction product is recrystallized from 1 part benzene to yield 2,2-bis(trifluoromethyl)-4-carbamoyloxymethyl-1,3-dioxolane (m.p. 52°-54° C.)
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
60 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][N:46]=1>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:49]([C:48]2[CH:47]=[N:46][C:45]([Cl:44])=[CH:53][CH:52]=2)=[O:50])([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.34 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (12 mL) and N-ethyl diisopropylamine (0.48 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.138 g, 2.58 mmol, 1.1 equiv; BOP reagent) 6-chloro-nicotinic acid (0.369 g, 2.34 mmol, 1.0 equiv) and the reaction mixture stirred at rt for 12 h. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.63 g (74%) of the title compound as off-white solid. MS (ISP): 365.1 [M+H]+