Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[N:28]=[C:27]([CH2:29][N:30]5[CH2:31][CH:32]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH2:33]5)[S:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc(-c2nc(N3CCOCC3)c3nc(CN4CC(N5CCOCC5)C4)sc3n2)n2ccnc2c1
Yield: 55.4 %

Procedure:
A mixture of 7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine (0.25 g, 0.37 mmol), 5-bromoimidazo[1,2-a]pyridine (0.082 g, 0.41 mmol), copper(I) 2-thiophene carboxylate (0.015 g, 0.075 mmol) and Pd(PPh3)4 (0.044 g, 0.037 mmol) in dioxane (3 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 700 as a yellow solid (0.101 g, 55%). LCMS (Method E): RT=3.98 min, [M+H]+ 493.15. 1H NMR (CDCl3, 400 MHz) δ 9.16 (s, 1 H); 7.98 (dd, J=7.2, 1.2 Hz, 1 H); 7.81 (d, J=8.9 Hz, 1 H); 7.76 (d, J=1.2 Hz, 1 H); 7.33 (dd, J=8.9, 7.2 Hz, 1 H); 4.47-4.32 (m, 4 H); 4.04 (s, 2 H); 3.89 (t, J=4.6 Hz, 4 H); 3.74 (t, J=4.6 Hz, 4 H); 3.69 (t, J=6.4 Hz, 2 H); 3.23-3.15 (m, 2 H); 3.14 (t, J=6.4 Hz, 1 H); 2.40-2.36 (m, 4 H)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[F:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=[N:16][CH:17]=1.[F:32][C:33]1[C:42]2[C:37](=CC=CC=2)[C:36]([C:43](Cl)=[O:44])=[CH:35][CH:34]=1.Cl>C1COCC1.C(Cl)Cl>[F:32][C:33]1[CH:42]=[CH:37][C:36]([C:43]([CH:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:15]3[N:16]=[CH:17][C:12]([F:11])=[CH:13][N:14]=3)[CH2:23][CH2:22]2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:44])=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCN1CCN(c2ncc(F)cn2)CC1
Reactant: O=C(Cl)c1ccc(F)c2ccccc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCN(c2ncc(F)cn2)CC1)C(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a cold (-78° C.) solution of lithium 1,1,1,3,3,3-hexamethyl disilazane in tetrahydrofuran (27.4 mL, 1N, 27.4 mmol) kept under Ar atm was added dropwise (10 min) a solution of ethyl 4-(4-(5-fluoro-2-pyrimidinyl)piperazin-1-yl)butanoate (3.7 g, 12.5 mmol) in dry THF (12 mL). The reaction mixture was stirred 0.25 h at -78° C. and then treated dropwise (10 min) with a solution of 4-fluoro-1-naphthoyl chloride (2.6 g, 12.5 mmol) in dry THF (10 mL). The reaction was stirred -78° C. for 0.5 h then the cooling bath was removed. When the temperature of reaction mixture reached 0° C., HCl solution (40 mL, 0.3N) was added slowly followed by CH2Cl2 (350 mL); the organic phase was separated and aqueous phase was extracted with CH2Cl2 (120 mL). The organic extracts were combined, washed with water (2×45 mL) and brine, dried (MgSO4) and concentrated under reduced pressure to a crude mixture which was purified on a silica gel pad (8.7×2.5 cm). Evaporation of appropriate fractions gave 2.8 g (48%) of the desired product compound which was recrystallized from EtOH to give an analytical sample; mp 95°-6° C.; 1H NMR (CDCl3, 200 MHz) δ: 1.08 (t, J=7.1 Hz, CH3, 3H), 2.1-2.7 (m, 8H), 3.5-3.8 (m, 4H), 3.9-4.3 (m, 2H), 4.5-4.7 (m, 1H), 7.1-7.25 (m, 1H), 7.5-7.8 (m, 2H), 8.17 (s), 8.0-8.02 (s and m, 4H), 8.6-8.7 (m, 1H); IR (KBr) ν: 1740 (C=O, 1682, 1630, 1611, 1600, 1578, 1554, 1510 cm-1 ; UV (CH3CN) λ: 224 (ε 43570), 242 (ε 37740), 304 (ε 9084);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]2[CH2:25][CH2:24][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][N:8]([C:6]4[CH:7]=[C:2]([NH:1][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][CH:37]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=5)[CH:3]=[CH:4][C:5]=4[CH3:26])[CH2:25][CH2:24][C:11]=3[N:12]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-(4-chloro-phenyl)amine (54.87 mg, 0.15 mmol), 3-Trifluoromethylbenzoic acid (28.51 mg, 0.15 mmol), and Diisipropylethylamine (DIPEA)(78 μl, 0.45 mmol) in DMF (7.5 ml) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (59 mg, 0.15 mmol) and the reaction mixture is stirred for 3 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform to give of N-{3-[2-(4-chlorophenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-methyl-phenyl}-3-trifluoromethylbenzamide [13] as a pale yellow solid. [Yield: 60.6 mg, 75.2%]
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br:11]Br>>[C:1]1([S:7]([Br:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: BrBr
Agent: [Na+]
Product: O=S(=O)(Br)c1ccccc1

Procedure:
Benzenesulfonyl bromide was synthesized with 1316.0 g of the mother liquid containing sodium benzenesulfinate by procedures similar to those of the fourth step and the fifth step of Example 1 except that bromine was used instead of chlorine in the fifth step. Thus, 36.0 g of benzenesulfonyl bromide was yielded. Gas chromatographic analysis revealed that the concentration of benzenesulfonyl bromide in the organic layer was 81.3% (weight; 29.27 g, 0.133 mole), and the yield was 94.4%.
Reaction SMILES: [NH:1]([C:3]([C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][N:7]([OH:10])[CH:8]=[O:9])=[O:4])[NH2:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH2:16]([NH:2][NH:1][C:3]([C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][N:7]([OH:10])[CH:8]=[O:9])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC[C@H](CN(O)C=O)C(=O)NN
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCCCC[C@H](CN(O)C=O)C(=O)NNCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[(R)-2-(Hydrazinocarbonyl)-heptyl]-N-hydroxy-formamide (50 mg, 0.23 mmoles) and benzaldehyde (24 mg, 0.23 mmoles) were dissolved in methanol (2 mL) under argon in the. presence of 4 Å molecular sieves (50 mg), stirred for 1 hour and cooled to 0° C. To the mixture was added one crystal of methyl orange indicator and enough methanolic HCl to keep the solution acidic (red color). Sodium cyanoborohydride (17 mg, 0.28 mmoles) was added, along with enough methanolic HCl to keep the solution acidic (red indicator). The system was warmed to room temperature, stirred for two days, neutralized with sodium bicarbonate solution, and extracted with ethyl acetate (3×). The organic layer was dried over anhydrous sodium sulfate, concentrated to dryness and purified by prep hplc to afford the title compound. MH+308.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[NH3:17]>CO>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([NH2:17])=[O:15])[NH:7]2
Reactant: COC(=O)c1cc2c(OC)c(C)ccc2[nH]1
Reactant: N
Solvent: CO
Product: COc1c(C)ccc2[nH]c(C(N)=O)cc12

Procedure:
80 mg of methyl 4-methoxy-5-methyl-1H-indole-2-carboxylate (0.39 mmol) was heated at 80 degrees in a sealed tube with 1 mL of 7M ammonia in methanol. After one week reaction the solvent evaporated to produce 79 mg of 4-methoxy-5-methyl-1H-indole-2-carboxamide that was used without purification in the next step.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36]
Reactant: CC(=O)OCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Yield: 89.5 %

Procedure:
A mixture of (3S)-1-(2-acetoxyethyl)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.80 g) and potassium carbonate (0.30 g) in 85% aqueous ethanol (30 ml) was heated at 65° to 70° C. for 1 hour under stirring. After cooling, ethanol was removed under reduced pressure, and to the residue was added water. The aqueous mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Removal of the solvent afforded a light yellow amorphous powder, which was chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (3:1). The fractions containing the desired product were combined and evaporated to give (3S)-1-(2-hydroxyethyl)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.47 g) as a colorless amorphous powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([F:19])([F:18])[F:17])[NH:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.ClC1N=CN=C(Cl)C=1>C1COCC1>[Cl:30][C:31]1[N:32]=[C:33]([S:38][CH3:39])[N:34]=[C:35]([N:12]2[C@H:13]([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:15][C@H:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[CH2:11]2)[CH:36]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=C(NC1CCCCC1)[C@H]1CC[C@@H](C(F)(F)F)NC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Clc1cc(Cl)ncn1
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To cis-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (1.0 g, 3.2 mmol) in THF (15 mL) was added 1M LiHMDS in THF (11 mL, 11.00 mmol) at room temperature. After 5 minutes, 4,6-dichloro-2-(methylthio)pyrimidine (0.620 g, 3.18 mmol) was added. After 10 minutes, LCMS analysis of the reaction mixture indicated the presense of ˜85% desired product+13% of dichloropyrimidine SM. The reaction mixture was poured onto saturated NH4Cl and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. A solid cartridge was prepared by adding EtOAc (˜200 mL) to the crude and SiO2 (3 g). The mixture was concentrated. Flash chromatography (100% Hexanes to 50% EtOAc in Hexanes, then 100% EtOAc) afforded the title compound (690 mg) as an off-white solid. LC-MS (ES) m/z=437, 439 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:14]=[CH2:13]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 50 °C
Yield: 78.4 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile [164 mg, 1.0 mmol, prepared as described in Yasubiro Imakura et. al. Chem. Pharm. Bull 40 (7), 1691-1696 (1992)] in anhydrous DMF (2 mL) was added allyl bromide (0.11 mL, 1.3 mmol), followed by K2CO3 (166 mg, 1.2 mmol). The resulting suspension was heated to 50° C. under Argon for 4 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 30% to 60% EtOAc/hexane to furnish the title compound (160 mg, 80% yield) as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:18]1([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: COc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 67.2 %

Procedure:
The title compound (96.8 mg) was prepared as in Example 177, Steps C and D, using 207 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 224.1 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C20H27N3O, 325.45; found, m/z 326.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.25 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 4.00-3.92 (m, 1H), 3.87 (s, 3H), 3.45-3.40 (m, 2H), 3.22-3.17 (m, 2H), 2.81-2.75 (m, 2H), 1.96-1.65 (m, 7H), 1.29-1.19 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:17]=2[N:18]=1.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[Cl:12][C:13]1[N:14]=[C:15]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=2[C:4]([NH2:6])=[O:5])[C:16]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:23])=[O:24])[C:17]=2[N:18]=1
Reactant: NC(=O)c1c(N)cccc1F
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
A mixture of 2-amino-6-fluorobenzamide (10 g, 64.9 mmol, Piedmont or Ryan Scientific) and 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (17.7 g, 51.7 mmol) was taken up into trifluoroethanol (400 mL) and trifluoroacetic acid (20 mL, 260 mmol). The resulting yellow slurry was heated at 80° C. After heating for 30 minutes a clear brown solution was obtained, which was heated at 80° C. for 18 h, then at the reflux temperature for an additional 6 h. The resulting slurry was cooled to 0° C. and filtered. The filtrate was concentrated down to 200 mL volume, heated at 80C for 20 h, cooled to 0° C., then filtered. The two crops of solids were combined, taken up into isopropanol (150 mL), heated at the reflux temperature for 4 h, then filtered to give 13 g (55%) of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a pale yellow solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.71 (d, J=3.66 Hz, 1 H), 7.12-7.17 (m, 1 H), 7.45-7.48 (m, 2 H), 7.49-7.52 (m, 1 H), 7.61 (d, J=7.87 Hz, 1 H), 7.67 (d, J=4.03 Hz, 1 H), 7.80 (s, 1 H), 7.89 (s, 1 H), 7.95-7.98 (m, 2 H), 10.47 (s, 1 H).
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([NH:12][NH2:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNc1ncccc1Cl
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 65 °C
Yield: 54.8 %

Procedure:
To a 1000 mL flask, anhydrous ethanol (300 mL), sodium ethoxide (16.97 g, 0.249 mol) and 3-chloro-2-hydrazinylpyridine (30.47 g, 98%, 0.21 mol) were added. The reaction mixture was heated to reflux for 5 minutes. Diethyl maleate (36.0 g, 0.31 mol) was added dropwise and heated to reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (45.36 g, 0.42 mol) and then diluted with 300 mL water. The reaction mixture was cooled down to room temperature, solid is separated to be filtered, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate (31.03 g) as an orange solid in 52% yield. HPLC area normalization method content is 94% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:58][C:59]([NH2:61])=[O:60]>CN(C)C=O.C(OCC)(=O)C>[C:59]([CH2:58][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)(=[O:60])[NH2:61]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (50.0 mg, 0.081 mmole, example 205) and potassium carbonate (22.4 mg, 0.162 mmole) in N,N-dimethylformamide (4 mL) was added iodoacetamide (29.8 mg, 0.162 mmole, Aldrich). The mixture was stirred at room temperature overnight and diluted with ethyl acetate, washed with water, brine and concentrated. The crude product was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in dichloromethane) to give the title compound (40.5 mg, 74% yield). HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2924.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=3[C@H:19]3[CH2:23][N:22]([CH3:24])[C:21](=O)[C@@H:20]3[C:14]=2[CH:13]=1.[OH-].[Na+]>O1CCCC1.O.C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=3[C@H:19]3[CH2:23][N:22]([CH3:24])[CH2:21][C@@H:20]3[C:14]=2[CH:13]=1
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Aluminum chloride (6.9 kg) is added in portions to tetrahydrofuran (100 L) at 0° C. Stirring is continued and a 10% solution of lithium aluminum hydride in tetrahydrofuran (35.0 L) is added keeping the temperature below 10° C. The mixture is cooled to 0° C. and stirred for 15 minutes. A solution of trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (IV) (10.0 kg) in tetrahydrofuran (100 L) is added to the mixture while keeping the temperature below 15° C. Tetrahydrofuran (5 L) is added, stirring is continued for 1 hour at 10° C., and 0.6 N sodium hydroxide solution (100 L) is added keeping the temperature below 10° C. Stirring is continued for 15 minutes at 20° C. and toluene (150 L) and of water (100 L) are added. Stirring is continued for 15 minutes at 20° C. and the salt layer is separated. The salt layer is extracted with toluene (2×50 L). The combined filtrates are separated and the aqueous layer is extracted with of toluene (50 L). The combined organic layers are evaporated in vacuum at 70° C. to give trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (A) (9.4 kg, 99%); 1H-NMR (400.13 MHz in CDCl3 relative to TMS) δ 2.54 (s, 3H), 3.15 (m, 2H), 3.25 and 3.61 (2×M, 4H), 7.01-7.36 (m, 7H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([N:25]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:26]1[CH:31]=[C:30](B2OCC(C)(C)CO2)[CH:29]=[CH:28][C:27]=1[N+:40]([O-:42])=[O:41])#[N:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11]([C:30]2[CH:29]=[CH:28][C:27]([N+:40]([O-:42])=[O:41])=[C:26]([N:25]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:23]#[N:24])[CH:31]=2)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CN(C#N)c1cc(B2OCC(C)(C)CO2)ccc1[N+](=O)[O-]
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc([N+](=O)[O-])c(N(C#N)CC(C)C)c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Heat 1-benzyl-2-methyl bromo-5-(2,4-difluorophenyl)-1H-imidazole (0.321 g, 0.885 mmol), N-[cyano]N-[isobutyl]2-nitro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)aniline (0.352 g, 1.06 mmol), palladium(II)acetate (0.0099 g, 0.044 mmol), di-tert-butylphosphinoferrocene (0.058 g, 0.177 mmol), and potassium carbonate (0.45 g, 3.26 mmol) in dioxane (10 mL) to 100° C. for 20 hours. Cool to room temperature and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures to provide 0.191 g (0.38 mmol) of the title compound.