Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23]C2[CH:20]([O:21]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[C:24](=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.C1OCCOCCOCCOCCOCCOC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][C@@H:20]([OH:21])[C@H:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[O:10][CH3:24])[CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(Br)cc1O
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Solvent: CCO
Product: COc1cc(Br)ccc1O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Yield: 68.4 %

Procedure:
Suspend 4-bromoguaiacol (1.19 g, 5.72 mmol) and 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (prepared according to Syn. Comm. V26, Is8, p 1499, 1996) (530 mg, 2.86 mmol) in ethanol (6 mL) and add cesium carbonate (2.33 g, 7.15 mmol) and 18-crown-6 (5 mg). Heat the reaction mixture at reflux temperature for four days. Filter the mixture and evaporate the filtrate. Purify by silica gel chromatography, eluting with 0-65% EtOAc in hexanes to give 760 mg (69%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 7.13 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.8, 2.3 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 5.42 (bs, 1H), 4.54 (m, 1H), 4.10 (m, 1H), 3.74 (s, 3H), 3.54 (td, J=12.6, 4.1, 1H), 3.40 (td, J=12.6, 4.1, 1H), 3.31 (m, 1H), 3.22 (m, 1H), 2.47 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:13]([Cl:18])(Cl)(Cl)(Cl)[Cl:14].C(O)=[O:20].Cl>C(Cl)(Cl)(Cl)Cl>[Cl:14][P:13]([Cl:18])([NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)=[O:20]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccc([N+](=O)[O-])cc1

Procedure:
To a suspension of 68 g (0.41 mole) of 4-nitrobenzamide in 400 ml of AR carbon tetrachloride at 48° was added portionwise 85.2 g (0.41 mole) of phosphorus pentachloride. The reaction was heated at 65°-70° for 50 min., then cooled to 25°-30°. Added dropwise while maintaining a temperature of 30°, 19.4 g (0.41 mole) of 97% formic acid. After the evolution of gas (CO and HCl) had ceased the reaction was filtered, washed with AR carbon tetrachloride and air-dried to give 103.2 g, m.p. 134°-135.5°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([O:20][CH:21](OCC)[CH3:22])[CH3:19])=[CH:12][CH:11]=2)[CH:3]=1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[OH-].[Na+]>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([O:20][CH:21]=[CH2:22])[CH3:19])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CCOC(C)OC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=COC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(1-ethoxyethoxy)propoxy)benzyl)-benzene (550 mg, 1.3 mmol) in dichloromethane (10 mL) at 0° C. under argon was added triethylamine (0.2 mL, 2.2 mmol), followed by trimethylsilyltrifluoromethane sulfonate (240 mg, 2.2 mmol). After 1 h, 1.0 M sodium hydroxide (4 mL) was added, followed by diethyl ether (20 mL). The organic phase was separated, dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography (PE/EA=10:1) to obtain intermediate DA (290 mg, yield 59%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:2]1.[CH:15]1[N:19]=[CH:18][N:17]([C:20](N2C=NC=C2)=[O:21])[CH:16]=1>C(#N)C>[N:17]1([C:20]([O:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH3:13])=[O:21])[CH:16]=[CH:15][N:19]=[CH:18]1
Reactant: CC(O)c1ccc(-c2ccoc2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47a (110 mg, 0.58 mmol), CDI (471 mg, 2.91 mmol) and acetonitrile (7 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:2) as eluent. White solid. Yield: 40 mg, 24%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.78 (d, J=6.6 Hz, 3H), 6.11 (q, J=6.7 Hz, 1H), 6.89 (dd, J=1.9, 0.9 Hz, 1H), 7.07 (dd, J=1.6, 0.6 Hz, 1H), 7.40-7.44 (m, 1H), 7.46-7.52 (m, 2H), 7.74 (dd, J=8.4, 2.7 Hz, 1H), 8.04 (dd, J=1.4, 0.8 Hz, 1H), 8.12-8.18 (m, 1H), 8.67 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.4, 74.9, 108.5, 117.0, 119.9, 126.5, 130.8, 132.8, 134.6, 137.0, 141.6, 144.0, 147.9, 148.0, 152.4; MS (ESI): m/z=284.25 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29](O)=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29]([NH2:34])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: O=C(O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 3.3 g (7.16 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid (I.25b), 20 mL of dimethylformamide and 3.26 g (8.59 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) was added 0.759 g (14.52 mmole) of ammonium chloride followed by 3.74 mL (21.48 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour and then diluted with 500 mL of water. The suspension was stirred for 30 minutes. The precipitate was collected by filtration to afford 3.2 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide as an off-white solid (I.25c).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:19])([CH2:13]4)[CH2:11]3)[CH2:5][CH2:4]1.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30])=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]23[CH2:18][CH:14]4[CH2:13][C:12]([NH:19][CH2:21][C:22]([N:24]5[CH2:28][CH2:27][CH2:26][C@H:25]5[C:29]#[N:30])=[O:23])([CH2:11]2)[CH:16]([CH2:15]4)[CH2:17]3)[CH2:5][CH2:4]1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: CN1CCN(CC23CC4CC(C2)C(N)(C4)C3)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(CC23CC4CC(C2)C(NCC(=O)N2CCC[C@H]2C#N)(C4)C3)CC1
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a stirred solution of the hydrochloride (0.33 g, 0.92 mmol) obtained in Step II, in DMSO (3.7 mL) at room temperature under nitrogen atmosphere (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.92 mmol) and K2CO3 (0.76 g, 5.53 mmol) were added. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[(4-methylpiperazin-1-yl) methyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.12 g) in 47% yield. m/z (M+1) 386; 1H NMR (CDCl3+CD3OD) 300 MHz δ 4.78 (d, J=5.7 Hz, 1H), 3.85-3.50 (m, 4H), 3.30-3.10 (m, 5H), 2.85-2.70 (m, 8H), 2.52-2.45 (m, 2H), 2.38-2.20 (m, 4H), 2.10-1.90 (m, 4H), 1.70-1.40 (m, 5H), 1.40-1.27 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4c3)c2cc1OC
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (232 mg, 1.06 mmol) in toluene (4.5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.55 mL, 1.10 mmol) at RT followed by 2-(bromomethyl)naphthalene (252 mg, 1.14 mmol) and the mixture was stirred at 110° C. for 15 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) before extraction with CH2Cl2 (50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 210 mg of 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (8 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford after drying 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol hydrochloride 17 as a yellow solid (230 mg, 55% yield).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[S:87]1[CH2:92][CH2:91][N:90]([CH2:93][C:94](O)=[O:95])[CH2:89][CH2:88]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][N:90]1[CH2:91][CH2:92][S:87][CH2:88][CH2:89]1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CN1CCSCC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCSCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-thiomorpholinoacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 671.8 (M−H)−, 2.37 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.47 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d, J=4.3 Hz, 1H), 4.75 (s, 1H), 3.79-3.63 (m, 2H), 3.58 (td, J=6.5, 12.9 Hz, 1H), 3.47-3.35 (m, 3H), 2.95 (br. s., 4H), 2.68-2.57 (m, 2H), 2.37 (dd, J=8.4, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.92-1.82 (m, 2H), 1.81-1.76 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.69-1.64 (m, 1H), 1.60-1.31 (m, 12H), 1.30-1.22 (m, 1H), 1.19-1.11 (m, 2H), 1.09 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][NH:19][CH3:20].CCN(CC)CC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][N:19]([CH3:20])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CNCc1cc(Cl)cc(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc(Cl)cc(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a stirred solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.96 g, 5 mmol) in CH2Cl2 (20 mL) was added a solution of 3,5-dichlorobenzyl-methylamine hydrochloride (1.133 g, 5 mmol) and Et3N (2 mL) in CH2Cl2 (25 mL). The addition flask was rinsed with CH2Cl2 (5 mL) and added to the reaction mixture. After 2 h, the reaction mixture was concentrated and the resulting residue was triturated with ether (100 mL), filtered and concentrated to give the desired product as a viscous brown oil (1.70 g, 100% yield). 1HNMR (300 MHz, CDCl3) δ: 7.30–7.27 (1H, m), 7.16 (1.5H, br s), 7.06 (0.5H, s), 6.17 (0.66H, s), 6.07 (0.34H, s), 4.59 (1.33H, s), 4.53 (0.67H, s), 3.03 (2H, s), 2.97 (1H, s), 1.74 (4H, s), 1.70 (2H,s).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[K+].C[Mg]Cl.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1C(Cl)=O>O1CCCC1>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3]([C:15]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:14]=1[Cl:13])=[O:4]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: COC(=O)CC(=O)[O-]
Agent: C[Mg]Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A 400 liter glass-lined reactor was charged with 257 liters of tetrahydrofuran and 32.05 kg (205.2 moles, 2.1 eq) of potassium methyl malonate. While the reaction mixture was cooled to maintain the temperature below 40° C., 82.5 liters of 2.4M (198 moles, 2.02 eq) methyl magnesium chloride were added over about 1.5 hours. The addition resulted in a thick slurry of the malonate magnesium complex. The slurry was stirred for 0.5 hours at about 32° C. Then 2-chloro-4,5-difluorobenzoyl chloride (20.7 kg, 98.1 moles) was added with cooling, maintaining the temperature between 32° and 23° C. After the addition was complete, the turbid solution was stirred for 0.5 hours and was quenched into 154 1 of 2N HCl. The product was extracted with 114 1 of toluene. The organic layer was washed with 91 1 of saturated sodium bicarbonate/sodium chloride solution. The product/organic layer held 2.5% water (by Karl Fischer titration) which was higher than usual (i.e. 0.5 to 1.5%), so it was washed with 76 1 of saturated sodium chloride solution. The organic layer was concentrated by vacuum distillation to about 26 1 and 28 1 of isopropyl alcohol were then added. The product was crystallized by cooling to -10° to -12° C. The product was collected by filtration and then vacuum dried to give 22.3 kg (89.7 moles, 91.4 % yield) of the title compound. The high field NMR of the product was typical of that for a mixture of the keto (60%) and enol (40%) forms of the title compound. 300 MHz 1H NMR (CDCl3): 12.4 (s, 0.4H) , 7.5 (m, 1H), 7.3 (m, 1H), 5.6 (s, 0.4H), 4.0 (s, 1.2H), and the methyl esters 3.7 (s, 1.3H), 3.6 (s, 1.7H).
Reaction SMILES: O=C(NCCC)C(N[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([NH:22]C(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)=[CH:18][C:16]=2[CH:17]=1)=[O:12])C1C=CC=CC=1.[H][H].C1C[O:50][CH2:49]C1>[Pd]>[CH3:49][O:50][C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=2[CH:17]=1)=[O:12]
Reactant: CCCNC(=O)C(NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1)c1ccccc1
Reactant: C1CCOC1
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)c1cc2cc(N)ccc2o1

Procedure:
The product from step (a) (6.9 g) was dissolved in THF (200 mL), followed by the addition of 10% Pd/C (1 g), and the resulting reaction mixture was hydrogenated under 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration through celite, and the solvent was removed in vacuo to provide 5.9 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:1][C:2]2[C:3]([O:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: COC(=O)C(C)Oc1nc(C)ncc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 1 hour at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1oc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1oc(COc2ccc(/C=C/C=C/C#N)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile. Then, according to the method described for Reference Example 16, (E,E)-5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile was subjected to catalytic reduction to give 5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]valeronitrile. Recrystallization from ethyl acetate--ether--hexane gave colorless prisms, m.p.65°-66° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]12CCCN=C1C[CH2:30][CH2:29][CH2:28][CH2:27]2>C(#N)C=CC>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:29]([CH3:30])[CH2:28][C:27]#[N:26])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: CC=CC#N
Product: CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 55 °C
Reaction time: 17.5 h
Yield: 247.3 %

Procedure:
Into a 250 mL three-neck round bottom flask equipped with a stir bar, condenser, thermocouple and nitrogen inlet was charged 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (5, 10.3 g, 0.033 mol), 2-butenenitrile (36, 3.0 mL, 0.037 mmol, 1.12 equiv) and acetonitrile (100 mL, 2.0 mol) at room temperature. The resulting mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.0 mL, 0.013 mol, 0.4 equiv) and was subsequently warmed to 55° C. The reaction mixture was stirred at 55° C. for 15-20 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to yield an orange oil. The crude product was then purified by flash column chromatography (SiO2, 40-80% ethyl acetate/hexane gradient elution) to afford 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37, 12.3 g, 12.62 g theoretical, 97.5% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For 37: 1H NMR (CDCl3, 400 MHz) δ ppm 8.84 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.39 (d, 1H, J=3.8 Hz), 6.79 (d, 1H, J=3.8 Hz), 5.67 (s, 2H), 4.77 (m, 1H), 3.53 (t, 2H, J=8.2 Hz), 3.05 (dd, 1H, J=16.8, 6.2 Hz), 2.98 (dd, 1H, J=16.8, 6.3 Hz), 1.79 (d, 3H, J=6.5 Hz), 0.91 (t, 2H, J=8.3 Hz), −0.068 (s, 9H); C19H26N6OSi (MW, 382.53), LCMS (EI) m/e 383 (M++H).
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([F:50])[C:44]=1[Cl:51]>>[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:45]([F:50])[C:44]=1[Cl:51]
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)c(Cl)c1F
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Br)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(4-bromo-3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 4-bromo-3-chloro-2-fluoro-aniline; other starting materials were prepared as example 1.
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[NH:13][O:14][CH3:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC1c2ccccc2CCCC1F
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a stirred solution of N-(6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (0.100 g; 0.48 mmol), prepared as described in example P2b and triethylamine (0.073 ml; 0.53 mmol) in dichloromethane (1 ml) under nitrogen at 0° C. was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.093 g; 0.48 mmol). The reaction mixture was stirred at 20° C. for 15 h under nitrogen. The solvent was removed in vacuo to afford a sticky oil which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 95:5 to 0:100) to afford 0.134 g (76% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as an oil.