Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
2,4-difluoroaniline (9.0 g, 69.71 mmol) and pyridine (5.6 mL, 69.71 mmol) were dissolved in dichloromethane (45 mL) and the solution was cooled to 0° C. A solution of cinnamoyl chloride (13.04 g, 76.7 mmol) dissolved in dichloromethane (45 mL) was added dropwise, and after the addition the reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 and the layers were separated. The organic layer was washed with 1 M HCl then dried over Na2SO4 and concentrated in vacuo to provide a white solid. The solid was slurried in dichloromethane (150 mL), stirred for 30 minutes, and then hexanes (150 mL) were added. After stirring several minutes, the white solids were collected by filtration, washed with dichloromethane and air-dried to provide 13.5 g of the desired product. MS APCI (−) m/z 258.0 (M−1) detected.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1>O1CCOCC1>[C:1]([NH:5][S:16]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1)(=[O:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COc1cc(OC)cc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Product: COc1cc(OC)cc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C

Procedure:
A solution of 7.3 gm (0.1 mol) of tert. butylamine in 20 ml of dioxane was added dropwise to a solution of 10.0 gm (42 mmols) of 3,5-dimethoxy-benzene sulfonic acid chloride in 100 ml dioxane at 40° C. over a period of 15 minutes. After the reaction temperature began to drop the reaction mixture was heated at 45° C. for 1.5 hours and at 60° C. for 2 hours. After cooling and filtering, the filtrate was evaporated in vacuo. The residue was recrystallized from cyclohexane.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[C:7][CH2:8][OH:9]>CCO.[Pd]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCC#Cc1nccs1
Agent: [Pd]
Solvent: CCO
Product: OCCCc1nccs1

Procedure:
Pd on charcoal (0.5 g) was added to a sol. of 3-thiazol-2-yl-prop-2-yn-1-ol (2.31 g, 16.6 mmol) in EtOH (85 mL), and the mixture was subjected to an atmosphere of H2 overnight.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:33])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:32])[CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)[CH2:14][CH2:13]1>CO>[NH2:21][CH2:20][CH:19]([OH:32])[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:33])[CH2:13][CH2:14]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CNC(=O)OCc2ccccc2)CC1
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CN)CC1
Reaction time: 2 h

Procedure:
To a solution of N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(phenylmethoxy)-carbonylamino]propyl}piperazinyl)acetamide in methanol (70 mL) at room temperature was added under a steady flow of nitrogen Pd/C (10% w/w, 0.337 g). Hydrogen gas was bubbled through the reaction mixture via a septum with a needle as outlet for 2 minutes, and the reaction was stirred under a positive hydrogen pressure for two hours. Nitrogen was blown over the suspension before it was filtered over celite. The filtrate was evaporated to give 2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)acetamide, a compound of formula (6), as a clear oil (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[OH:8])[NH:1][C:17](=[O:18])[O:19][CH:20]([CH3:22])[CH3:21]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-amino-2-chlorophenol (21.45 grams, 0.15 mole) in dry DMF (150 ml.) and pyridine (11.8 grams) is added at 0°C. slowly dropwise with stirring isopropyl chloroformate (16.5 grams, 0.016 mole). After 4 hours at 0° C. to 5°C., a further one gram of isopropyl chloroformate is added. The mixture is stirred at 25°C. for 16 hours, then poured into ice-dilute hydrochloric acid. After 4 hours stirring and scratching, a solid separates out and is filtered off. Crystallization from methanol gives 14.5 grams, 42%, melting point 89°C. to 90°C.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:7])[C:3]([O:5]C)=[O:4].[Li+].[OH-]>CO.O.CCOC(C)=O>[CH3:7][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)NC(=O)c1cnccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)c1cnccn1)C(=O)O
Temperature: 22 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of methyl 2-methyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoate (0.36, 1.6 mmol) in MeOH/H2O (2:1) (6.0 mL) was treated with LiOH (0.08 g, 3.2 mmol) and stirred at 22° C. After 12 h, the reaction was diluted with 1-O and EtOAc and the layers were separated. The aqueous layer was acidified with 1 M HCl in water (28 mL) to an approximate pH˜2. The aqueous was extracted with EtOAc (3×). These three combined extracts were dried (Na2SO4), filtered and concentrated to obtain the title compound (0.286 g, 88%).
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:19][CH:18]=[CH:17][CH:16]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:4]([C:3]1[N:22]([CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=1)[CH2:5][CH3:6]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCOCC1
Yield: 69.2 %

Procedure:
Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride (23 mg, 0.2 mmol) were added to a suspension of 4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the resulting solid was isolated by filtration to provide 2.26 g of 4-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH:6]1)=[O:4].[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:9]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[NH:6][CH:5]2[C:3]([OH:4])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1NC(CC(C)(C)Cc2ccc(OC)cc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 126b (4 g, 6.8 mmol) in tetrahydrofuran (60 mL) was added an aqueous solution (1 N) of NaOH (20 mL, 20 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 3 h. The “pH” of the mixture was adjusted to ˜4-5 by aqueous HCl solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid as a light yellow solid (4 g, 100%)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:40][N:39]=[N:38][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:8]1[N:5]2[N:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Cc1cnn2ccnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnn2c(Br)cnc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
To a stirred solution of 7-methylimidazo[1,2-b]pyridazine (30.1 mg, 0.226 mmol) (prepared as described by Pollak et al, Tetrahedron, 1968, 24, 2623) and sodium acetate (27.4 mg, 0.334 mmol) in glacial acetic acid (1 ml) was added dropwise, over 2 min, bromine (12.2 μl, 0.237 mmol). The mixture was stirred at room temperature for 20 min, then partitioned carefully between saturated aqueous NaHCO3 (15 ml) and ethyl acetate (20 ml). The aqueous layer, which had a pH of 9, was extracted further with ethyl acetate (2×20 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to leave 47.3 mg (99%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 2.45 (3H, s), 7.70 (2H, s), 8.30 (1H, s).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:37])[C:29]3[NH:34][C:33](=[O:35])[CH2:32][O:31][C:30]=3[CH:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C.CO>CN(C=O)C.O>[CH3:37][C:28]1[C:29]2[NH:34][C:33](=[O:35])[CH2:32][O:31][C:30]=2[CH:36]=[C:26]([O:25][C:21]2[CH:20]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[N:24]=[CH:23][N:22]=2)[CH:27]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2c1NC(=O)CO2
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2c1NC(=O)CO2

Procedure:
72 mg (0.28 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.22 mmol) 7-(6-chloropyrimidin-4-yloxy)-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 100 μL (0.58 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was combined with methanol and water. The precipitate formed was suction filtered, washed with methanol and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].P(Br)(Br)[Br:29]>ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:25][C:23]1[CH:24]=[C:2]([Cl:1])[C:3]([C:4]([C:6]2[C:14]3[C:9](=[C:10]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)=[O:5])=[C:21]([Cl:27])[CH:22]=1
Reactant: BrP(Br)Br
Reactant: O=C(c1c(Cl)cc(CO)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1c(Cl)cc(CBr)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Yield: 31.7 %

Procedure:
To a solution of N-{3-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (900 mg, 2.23 mmol) in dichloromethane and carbon tetrachloride (2:1) at 0° C., phosphorus tribromide (1200 mg, 0.42 mL, 4.455 mmol) was added drop wise over a period of few minutes, stirred the mixture at 0° C. to room temperature. On completion, the reaction was quenched by adding saturated solution of sodium bicarbonate and extracted with dichloromethane. Organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-{3-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (330 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]([Cl:33])=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxylic acid (126 mg, 0.37 mmol) from Step A and a drop of DMF (cat.) in methylene chloride (5 mL) was added oxalyl chloride (0.16 mL, 1.85 mmol). The reaction was stirred at rt for 2 h and was then evaporated to dryness in vacuo. The crude acid chloride was used directly in the subsequent amide formations.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][NH:30][CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.Br[CH2:36][CH2:37][OH:38].C(N(CC)CC)C>CN(C)C=O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][N:30]([CH2:36][CH2:37][OH:38])[CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: OCCBr
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(CCO)C2)C3)c2ncnc(N)c12
Temperature: 85 °C
Yield: 48.7 %

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile (0.015 g, 0.034 mmol) (from Example 46, Step 15) and 2-bromoethanol (0.0097 mL, 0.14 mmol) were combined in N,N-dimethylformamide (1 mL) with triethylamine (0.019 mL, 0.14 mmol) at room temperature. The reaction was heated to 85° C. and after heating for 2 hrs the reaction was concentrated in vacuo and the residue was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the desired compound as a white amorphous solid (0.008 g, 50%). LCMS calculated for C23H28ClN8O2 (M+H)+: m/z=483.2; found: 483.2.
Reaction SMILES: [C:1]([O:5]CC)(=O)[NH:2][NH2:3].Cl[C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[C:13]([CH3:15])[CH:14]=1>C(O)CCC>[CH3:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:11][N:10]2[C:1](=[O:5])[NH:2][N:3]=[C:9]2[CH:14]=1
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: Cc1cc2n[nH]c(=O)n2nc1-c1ccc(C#N)cc1

Procedure:
A 12.6 g. portion of ethyl carbazate is dissolved in 300 ml. of butanol. A 13.77 g. portion of 3-chloro-5-methyl-6-(p-cyanophenyl)pyridazine is added and the mixture is stirred at reflux for 18 hours. The mixture is cooled in ice and the solid is recovered by filtration and air dried, giving 6.3 g. of the desired product as a cream colored solid, m.p.>300° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution composed of 8.94 g (27.6 mmol) of (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 35.8 mL of 2,2-dimethoxypropane, and 2.5 mL of methylene chloride was added 269 mg (1.4 mmol) of p-toluenesulfonic acid-1H2O, and the mixture was stirred at 20° C. for 4 hours, after which 500 mL of saturated sodium hydrogen carbonate solution was added. The aqueous layer was separated and further extracted with 2 portions of methylene chloride, 20 mL each, and the organic layers were combined. The combined solution was dehydrated over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a colorless oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=10:1) to give 7.24 g of 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic tert-butyl ester (white solid). Yield: 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12.[C:32](O)(=[O:34])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12
Reactant: CC(=O)O
Reactant: CN1CCC(c2cc3c(-c4nc(NCC5CCNCC5)ccc4Cl)ccnc3[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CNc2ccc(Cl)c(-c3ccnc4[nH]c(C5CCN(C)CC5)cc34)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 165 (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added acetic acid (4 mg, 0.07 mmol) and triethylamine (0.1 mL) at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11 mg, 0.07 mmol) and N-hydroxybenzotriazole (10 mg, 0.07 mmol) were added and the mixture was stirred overnight. Purification by HPLC (Zorbax XDB C-18 (32) using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) afforded the title compound. 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.93 (m, 5H), 1.96 (s, 3H), 2.28 (d, J=13.73 Hz, 2H), 2.80 (d, J=3.97 Hz, 3H), 2.87-3.01 (m, 2H), 3.02-3.22 (m, 5H), 3.52 (d, J=11.60 Hz, 2H), 3.77 (d, J=13.12 Hz, 2H), 4.34 (d, J=12.82 Hz, 2H), 6.10 (s, 1H), 6.61 (d, J=9.16 Hz, 1H), 7.11-7.18 (m, 1H), 7.56 (d, J=9.16 Hz, 1H), 8.23 (d, J=5.19 Hz, 1H). LCMS: 481 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:29](=[CH:30][CH:31]=1)[O:28][C:21]1[C:22]([F:27])=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[N:32]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]3([C:7]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[C:13]([NH2:14])=[N:32]3)[C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([F:27])[C:21]=3[O:28][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: N#Cc1ncccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-BuLi (1.6 M in hexane; 0.174 ml, 0.278 mmol, Aldrich) was added dropwise to a solution of 3-bromopicolinonitrile (50.9 mg, 0.278 mmol, Alfa Aesar) in THF (5 ml) at −95° C. After 2 min a solution of N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (100 mg, 0.232 mmol, example x) in THF (3 mL) was added. After 5 min aqueous, saturated NH4Cl solution was added and the reaction mixture was allowed to warm to rt. EtOAc was added, the organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (20-100% EtOAc/hexanes). The title compound was obtained as a yellow solid (38 mg, 0.088 mmol). MS m/z=432.8 [M+H]+. Calculated for C18H9BrClFN4O: 431.65.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=O)[N:7](C)[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][CH2:8][NH:7][C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)NCCN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to example 730 (0.058 g, 42%). Mp 149-151° C.; LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 8.25 (s, 1H), 8.00 (s, 1H), 7.83 (d, 1H, J=7.58 Hz), 7.78 (s, 1H), 7.75 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.30 (t, 1H), 6.07 (t, 1H), 5.75 (s, 1H), 4.16-4.12 (t, 1H, J=8.08 Hz), 3.90 (s, 3H), 3.60-3.50 (q, 2H, J=11.87 Hz), 3.19 (s, 3H), 3.11 (s, 2H), 2.86 (s, 1H), 2.72 (s, 1H), 2.41-2.40 (d, 2H, J=6.57 Hz), 2.11-2.09 (d, 1H, J=8.84 Hz), 1.40-1.35 (d, 1H, J=8.84 Hz), 0.92-0.80 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.20-0.12 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[N-:8]=[N+:9]=[N-:10].[Li+].O>CN(C)C=O>[N:8]([CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])=[N+:9]=[N-:10]
Reactant: O=C1OCCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-γ-butyrolactone are dissolved in 2 ml of dimethylformamide and treated at 0° C. with 612 mg (12.5 mmol) of lithium azide. The mixture is stirred at room temperature for 2 h, treated with water and extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.