Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:22])[C:16]#[C:17][Si](C)(C)C)=[O:8].C([O-])([O-])=O.[K+].[K+].CCCCCC>CO.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:22])[C:16]#[CH:17])=[O:8]
Reactant: Cc1ncoc1C(=O)c1ccccc1C(C)C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: C#CC(C)c1ccccc1C(=O)c1ocnc1C
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 1.16 grams (3.72 mmol, 1.0 eq) of oxazole 11a in 19 mL of MeOH was stirred in a 50 mL round bottom flask at room temperature under argon. To this solution was added 1.54 grams (11.16 mmol, 3.0 eq) of K2CO3 forming a heterogenous mixture. This suspension was vigorously stirred at room temperature until the reaction was complete by TLC (1:1 hexane:EtOAc, Rf=0.50). Upon completion (˜1 hour), the mixture was diluted with EtOAc and washed with 1.0 M HCl. The aqueous layer was then extracted twice more with EtOAc and the combined organic fractions were washed with brine and dried over MgSO4. Concentration yielded 860 mg (97%) of 11b as a light brown oil. This material could be purified via silica gel chromatography (hexane/EtOAc), though often the material was used directly for subsequent transformations. 1H-NMR (500 MHz, CDCl3): 7.91 (s, 1H), 7.78 (1H, d, J=7.8 Hz), 7.54 (1H, t, J=7.6 Hz), 7.40 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz), 4.12 (1H, dq, J=7.0 Hz, 2.5 Hz), 2.38 (3H, s), 2.18 (1H, d, J=2.4 Hz), 1.51 (3H, d, J=6.8 Hz). 13C-NMR (500 MHz, CDCl3): 185.43, 152.17, 147.06, 145.38, 142.10, 136.17, 131.80, 128.50, 128.32, 126.68, 87.10, 70.17, 28.31, 24.65, 14.16. IR (cm−1): 3293 (w), 1653 (vs), 1579 (s), 1485 (m), 1443 (w), 1384 (m), 1356 (s), 907 (s). HRMS (EI) calcd. for C15H13NO2: 239.0946. found: 239.0936.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br.[OH-].[K+]>C(Cl)Cl>[Br:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(NC2CCCCC2)cc1
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(NC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
In a 100-mL flask, N-cyclohexyl-4-methylaniline (2.00 g, 10.6 mmol) was dissolved in methylene chloride (20 mL) and a solution of bromine (Br2) (1.69 g, 10.6 mmol) dissolved in methylene chloride (16 ml) was injected at 0° C. for 30 minutes. Then, the solution was further stirred for 2 hours, and a 1 N aqueous KOH (20 mL) solution was added. The solution added with the aqueous solution was transferred to a separatory funnel and extracted from methylene chloride (40 mL) twice. Water was removed from the combined organic layer over MgSO4, and filtered with a glass filter. The rotary evaporator was used to remove the solvent, thereby obtaining a residue. The obtained residue was separated by column chromatography to obtain colorless oil (2.67 g, 94%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])C.[OH-].[Na+]>CS(C)=O.O>[CH3:24][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9](=[O:17])[C:10]2[C:15]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16]
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(C)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc2c(C(=O)O)c(C)n(-c3ccccc3)c(=O)c12
Yield: 41.2 %

Procedure:
A solution of 3,8-dimethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl ester (200 mg, 0.62 mmol) in DMSO (3 ml) and aqueous 1N NaOH (2 ml, 2 mmol) was heated under microwave irradiation at +120° C. for 20 min and diluted with water (30 ml). Uncharged impurities were extracted with diethyl ether (30 ml) and the aqueous solution was poured into ice (50 g) with aqueous 2M HCl (10 ml). The obtained precipitate was filtered, washed with water and dried in vacuo to give 75 mg of yellow solid. Yield 41%. LC-MS (m/z) 293.9 (MH+); tR=1.09. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 2.74 (s, 3H), 7.3 (d, 1H), 7.32 (d, 2H), 7.48 (two overlapping m, 2H), 7.55 (t, 2H), 7.62 (t, 1H), 13.42 (b, 1H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)C.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)CCC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc2ccccc2c1

Procedure:
A solution of 19.5 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pentanoic acid ethyl ester and 7.8 g of lithium hydroxide (monohydrate) in 212 ml of methanol, 148 ml of tetrahydrofuran and 60 ml of water is stirred at room temperature for 75 minutes and then concentrated by evaporation. The residue is dissolved in 150 ml of water, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam. Rf value=0.50 (hexane/ethyl acetate 1:4). IR (CH2Cl2): 3053, 1712, 1639, 1406, 1341, 1278, 1183, 1141, 1108, 904, 849, 821 cm-1.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[CH3:13][O:14][CH:15]([O:19]C)[CH2:16][C:17]#[N:18].C(O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH2:12]([O:19][CH:15]([O:14][CH2:13][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COC(CC#N)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCC(OCc1ccccc1)OCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 871.1 %

Procedure:
4.95 g of p-toluenesulfonic acid monohydrate was added to 30.0 g of 3,3-dimethoxypropionitrile, 67.63 g of benzyl alcohol and 100 ml of toluene, and the mixture was stirred at 110° C. for 8 hours. The reaction solution was returned to room temperature, and 5.26 g of triethylamine was added. After stirring for 5 minutes, the reaction solution was transferred to a separating funnel and washed with 200 ml of an aqueous 1 mass % potassium carbonate solution once and then with 200 ml of distilled solution three times. Toluene and the unreacted raw materials were removed by distillation under reduced pressure to obtain 60.6 g of 3,3-dibenzyloxypropionitrile. Thereto, 21.36 g of acetyl chloride was added, and the mixture was stirred at 45° C. for 6 hours. The reaction solution was returned to room temperature, and unreacted acetyl chloride was removed by distillation under reduced pressure. The reaction solution was analyzed by 1H-NMR, as a result, the concentration of 3-chloro-3-benzyloxypropionitrile in the reaction solution was 54.2 mass %.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6]1.C[Si](C)(C)[NH:28][Si](C)(C)C>O1CCCC1>[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[N:23]([CH3:24])[N:22]([C:1]([NH2:28])=[O:2])[C:21](=[O:25])[CH:20]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc(-c2cc(=O)[nH]n2C)cc1OC1CCCC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)n(C(N)=O)n2C)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a 0° C. solution of phosgene (8.75 mmol, 4.61 mL; 1.9M solution in toluene) in dry tetrahydrofuran (30 mL) is added 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,2-dihydro-1-methyl-3H-pyrazol-3-one (7.0 mmol, 2.02 g) in dry tetrahydrofuran (15 mL) dropwise over 20 minutes. The resulting cloudy solution is stirred at 0° C. for 10 minutes and at room temperature for 1 hour after which a homogenous solution is obtained. The reaction mixture is cooled to 0° C. and hexamethyldisilazane (17.5 mmol, 2.82 g; 3.64 mL) in dry tetrahydrofuran (15 mL) is added in one portion. The resulting suspension is stirred at room temperature for 1 hour and then the volatiles are removed in vacuo. The residue is partitioned between 2% aqueous acetic acid (200 mL) and ethyl acetate (200 mL) and the aqueous phase is extracted with ethyl acetate (150 mL). The combined organic layers are washed with H2O (100 mL), dried (Na2SO4), and concentrated in vacuo to afford a tan solid. This material is triturated with ether and dried in vacuo for 1 hour at 60° C. to give the title compound as a white solid (1.80 g; 78%). 1H NMR (DMSO-d6, 400 MHz) δ7.23 (br s, 1H); 7.02 (m, 3H); 6.92 (br s, 1H); 6.08 (s, 1H); 4.86 (m, 1H); 3.78 (s, 3H); 3.72 (s, 3H); 1.88 (m, 2H); 1.70 (m, 4H); 1.56 (m, 2H). IR (KBr, cm-1) 3400, 3300, 3200, 2950, 1760, 1500, 1330, 1250, 1130.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:40]=2)[C:35](=[O:53])[N:34]1[CH2:54][C:55](O)=[O:56]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:55](=[O:56])[CH2:54][N:34]1[C:35](=[O:53])[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])[CH:37]=2)[C:33]1=[O:32]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol), DMAP (116 mg, 0.952 mmol), and EDC (182 mg, 0.952 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetic acid (225 mg, 0.571 mmol) was added portion wise, and the resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude was purified by flash chromatography on silica gel (DCM/MeOH 10/0.5). The resulting product was triturated with iPr2O affording after filtration 227 mg of crude desired product. A further purification by flash chromatography on silica gel (DCM/acetone 8/1) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.195 mmol, 40.9% yield, MS/ESI+ 796.02 [MH]+, [αD]=−30.31, c=0.415, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (s, 2H), 7.96 (d, 1H), 7.91 (d, 1H), 7.86 (dd, 1H), 7.40 (dd, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.92-6.99 (m, 1H), 7.08 (t, 1H), 6.86 (d, 1H), 6.84 (d, 1H), 6.00 (dd, 1H), 5.25 (s, 2H), 4.39 (s, 2H), 3.81-4.09 (m, 2H), 3.37 (dd, 1H), 3.21 (s, 3H), 3.21 (dd, 1H), 1.17-1.37 (m, 1H), 0.50-0.69 (m, 2H), 0.21-0.46 (m, 2H)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[C:11]([Cl:16])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(Cl)cc2)c(Cl)c(OCc2ccccc2)nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (11.8 g, 32.7 mmol), prepared as described in example 1B, in toluene (200 ml) was added Pd(PPh3)4 (2.26 g, 1.96 mmol). After 5 min, 2N aqueous sodium carbonate (65 ml, 130 mmol) solution was added, followed by 4-chlorophenylboronic acid (7.16 g, 45.8 mmol). The reaction was stirred at 100° C. for 6 h. After this time, the solution was cooled RT and the reaction mixture was diluted with ethyl acetate. The resultant solution was washed with water, saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified using silica gel column chromatography eluting with a gradient of 10-20% Ethyl acetate/Hexane to give the title compounds, 2-benzyl-6-(benzyloxy)-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one which were obtained as a mixture.
Reaction SMILES: C(OC([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([Br:19])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[Br:19][C:15]1[C:14]([CH3:20])=[CH:13][C:12]2[N:11]3[C@H:21]([CH3:23])[CH2:22][NH:8][CH2:9][C:10]3=[CH:18][C:17]=2[CH:16]=1
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Br)cc1n2[C@H](C)CNC1

Procedure:
A solution of 0.12 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 3 ml of a 2M solution of hydrochloric acid in ethyl acetate was stirred at room temperature under argon for 2 h. The precipitate was collected by filtration and dried to constant weight to yield the title compound (0.065 g) as off-white crystals. m.p.: 241° C. (dec.); ISP-MS: M+H=279.1; HNMR: (250 MHz, DMSO-d6, δ [ppm]) 1.50 (d, J=6.5 Hz, 3H); 2.45 (s, 3H); 3.48–3.74 (m, 2H); 4.36–4.58 (m, 2H); 4.74–4.89 (m, 1H); 6.35 (s, 1H); 7.54 (s, 1H); 7.78 (s, 1H)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:15]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)ON1C(=O)CCC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1-hydroxy-pyrrolidine-2,5-dione (1.23 mL, 10 mmol) in ethyl acetate (50 mL) was added 3-chlorocarbonyl-propionic acid methyl ester (1.15 g, 10 mmol). The mixture was cooled in an ice bath. Triethylamine (1.4 mL, 10 mmol) was added dropwise. The resulting suspension was stirred for 10 min in an ice bath and for 5 min without ice bath. The white solid was removed by filtration and washed with ethyl acetate (3×3 mL). The filtrate was concentrated to a white solid (2.32 g).
Reaction SMILES: Cl.C([O:5][C@H:6]([CH2:21][NH:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)([CH3:25])[CH3:24])[C@@H:7]([NH:17][C:18](=[O:20])[CH3:19])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)(=O)C.[OH-].[Na+]>CO>[Br:32][C:28]1[CH:27]=[C:26]([C:23]([NH:22][CH2:21][C@@H:6]([OH:5])[C@@H:7]([NH:17][C:18](=[O:20])[CH3:19])[CH2:8][C:9]2[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=2)([CH3:25])[CH3:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@@H](CNC(C)(C)c1cccc(Br)c1)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
To a solution of 107 mg (0.21 mmol) of hydrochloride 31 in 10 mL of methanol is added 1 mL of 1N NaOH. The mixture is stirred for 45 min at ambient temperature, then quenched with 1N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4, filtered and concentrated to a glassy solid. This is dissolved in methanol and treated with ethereal HCl to afford 70 mg (0.14 mmol, 68%) of compound 32 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.69 (s, 1 H), 7.56 (m, 2 H), 7.35 (t, J=8 Hz, 1 H), 6.71 (m, 2 H), 6.63 (m, 1 H), 3.98 (m, 2 H), 2.98 (m, 1 H), 2.8 (m, 1 H), 2.68 (m, 1 H), 2.39 (m, 1 H), 1.92 (s, 3 H), 1.83 (s, 6 H); IR (diffuse reflectance) 3311, 3283, 3257, 3249, 3058, 3007, 2757, 1655, 1646, 1628, 1596, 1551, 1459, 1116, 697 cm−1. MS (CI)m/z(rel intensity) 457 (15), 455 (MH+, 97), 458 (17), 457 (99), 456 (15), 455 (97), 377 (5), 259 (9), 216 (6), 214 (6), 96 (27), 69 (5). HRMS (ESI) calcd for C21H25N2O2F2Br+H1 455.1146, found 455.1145. Anal. Calcd for C21H25BrF2N2O2.HCl+H2O: C, 49.47; H, 5.54; N, 5.49; Found: C, 49.45; H, 5.50; N, 5.54.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH3:18][CH:19]([CH2:25][CH2:26][CH2:27][CH3:28])[C:20](OCC)=[O:21]>C(O)(=O)C>[O:21]=[C:20]([CH:19]([CH3:18])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithium (150 ml.) is added slowly to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of racemic ethyl 2-methylhexanoate (18.4 g.) in 50 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 16.7 g., b.p. 126°-129° C./1 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(CC(=O)N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of EXAMPLE 30B (1 g, 4.74 mmol) in thionyl dichloride (20 mL) was stirred at reflux for 3 hours. The solution was concentrated and the residue was diluted with dry dichloromethane (20 mL) and dropped into a solution of pyrrolidine (0.63 mL, 7.1 mmol) and diisopropyl ethylamine (1.7 mL, 9.5 mmol). The mixture was stirred at room temperature overnight and the mixture was washed with 1N aqueous hydrochloric acid (20 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated and the residue was purified by flash chromatography on silica gel eluting with 1/100 methanol/dichloromethane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCCC1.O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C[C@]1(c2cc(-c3cnn(-c4ccc(F)cc4)c3)ccc2F)N=C(N)OCC1(F)F
Temperature: 80 °C
Yield: 47.9 %

Procedure:
In a tube a mixture of (R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.1) (60 mg, 186 μmol), 1-(4-fluorophenyl)-1H-pyrazol-4-ylboronic acid (39.0 mg, 186 μmol), and cesium carbonate (242 mg, 743 μmol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for minutes. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.58 mg, 9.28 μmol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours. After evaporation, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 40:60 as the eluent. The (R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (36 mg, 48% yield) was obtained as a yellow solid. MS (ISP): m/z=405.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[F:23][C:24]1([F:30])[CH2:26][CH:25]1[C:27](O)=[O:28]>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([CH:25]4[CH2:26][C:24]4([F:30])[F:23])=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: O=C(O)C1CC1(F)F
Product: NC(=O)c1nc2n(c1CNC(=O)C1CC1(F)F)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2,2-difluorocyclopropanecarboxylic acid similarly to as described in example 2 with non-critical modifications to afford crude 10-bromo-3-((2,2-difluorocyclopropanecarboxamido)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 14 mg (33%) of 3-[[(2,2-difluorocyclopropanecarbonyl)amino]methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide M+1=473.2.