Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)(O)[C:32]#[N:33].C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:32]#[N:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(O)C#N
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCC1(CCC#N)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (1.25 g) dissolved in benzene (15 mL) were added acetone cyanohydrin (0.40 mL), tri-n-butylphosphine (1.08 mL) and 1,1-azobis(N,N-dimethylformamide) (754 mg). The solution was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added and insolubles were filtered off. The solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=5:1) to give the title compound (1.07 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([F:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:8]2([F:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(F)(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of the product of Example 1B (3.0 g, 11.04 mmol) in dioxane (50 mL) was added 3M HCl (50 mL). The reaction mixture was stirred overnight at ambient temperature, quenched with 3M NaOH (50 mL) and extracted with ethyl acetate. The organic layer was separated and concentrated. The resulting residue was chromatographed on silica gel eluting with 0%-30% ethyl acetate-hexane to obtain 95% pure desired product (2.6 g, 103%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ PPM 2.29-2.37 (M, 2H), 2.54-2.75 (M, 6H), 7.48 (DDD, J=8.14, 4.75, 1.02 HZ, 1H), 8.01 (DD, J=8.14, 1.70 HZ, 1H), 8.54 (D, J=4.75 HZ, 1H). MS (DCI) M/Z 228.01 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1)#[N:2].C[Si]([N:40]=[N+:41]=[N-:42])(C)C.C([Sn](=O)CCCC)CCC>C(COC)OC>[CH3:35][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:42][N:41]=[N:40][N:2]=2)=[CH:8][C:7]=1[NH:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(C#N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: Cc1ccc(-c2nnn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 80.9 %

Procedure:
A mixture of N-(5-cyano-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (273 mg, 0.600 mmol), prepared as described in Example 10, trimethylsilylazide (160 μL, 1.2 mmol), and dibutyltin oxide (36 mg, 0.060 mmol) in dimethoxyethane (6 mL) was reacted in the microwave reactor (120° C., 100 psi, 2). The reaction was then concentrated on a rotary evaporator and the residue was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (242 mg, 81%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.91 (s, 1H), 8.20 (d, 2H), 8.13 (d, 1H), 8.03 (d, 2H), 7.91-7.79 (m, 5H), 7.67-7.63 (m, 3H), 7.53 (d, 1H), 7.42 (ddd, 1H), 2.36 (s, 3H). MS (EI) for C29H22N8O: 499.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]([F:16])([F:15])[F:14].CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C@@:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:13]([F:16])([F:14])[F:15]
Reactant: O=C1Nc2ccc(Cl)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1

Procedure:
N-{[6-chloro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[NH2:22][CH2:23][CH:24]([OH:40])[CH2:25][O:26][C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[CH:30]1[C:31]2[NH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[C:27]([O:26][CH2:25][C@@H:24]([OH:40])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([S:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])=[CH:11][CH:10]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[CH:28][CH:29]=1
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1

Procedure:
The title compound was prepared from 4-(1,1-dimethyl-propyl)-benzenesulfonyl-piperidin-4-one and 1-amino-3-(9H-carbazol-4-yloxy)-propan-2-ol according to the reductive amination procedure of Intermediate 21 as an off-white solid; 1H NMR (DMSO) δ 0.55-0.63 )m, 3H), 1.27 (d, J=6.9 Hz, 6 H), 1.40-1.46 (m, 2H), 1.58-1.65 (m, 2H), 1.81(m, 2H), 2.38-2.45 (m, 2H), 2.63-2.82 (m, 2H), 3.07-3.13 (m, 2H), 3.51-3.54 (m, 1H), 3.90 (m, 1H), 4.08-4.13 (m, 2H), 4.66 (d, J=3.78 Hz, 1H), 5.07 (bs, 1H), 6.64 (d, J=7.95 Hz, 1H), 7.04-7.11 (m, 2H), 7.20-7.35 (m, 2H), 7.43 (d, J=8.07 Hz, 1H), 7.54-7.67 (m, 4H), 8.15 (d, J=7.71 Hz, 1H), 11.25 (s, 1H); MS (ES) m/z : 550.1 (MH+); HRMS for C31 H39N3O4S: 550.2751
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:16]([N+]([O-])=O)=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:11](=[O:20])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:21]=[C:10]1\[C:11](=[O:20])[NH:12][C:13]2[C:9]\1=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:16]=[CH:15][CH:14]=2
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#C[Si](C)(C)C)c21

Procedure:
Using Method D above, trimethylsilyl acetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.05 g, 6.42 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (0.23 g) and Cul (61 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 80° C. for 2 days to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(2-trimethylsilyl-ethynyl)-2H-indol-2-one. (Yield 1.3 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O:24]C)[O:22][CH3:23].C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:21]([O:22][CH3:23])=[O:24])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
Into a 25 ml, three-necked round-bottom flask fitted with a thermometer, vigreux column, distillation head, magnetic stirrer, syringe pump and nitrogen sweep was charged 5.0 g of 3-(4-benzyloxyphenoxy)-2-butanone and 10 g of dimethyl carbonate, and the solution heated to 90° C. Thereafter, 2.0 ml sodium methoxide in methanol was added over a period of 50 minutes via a syringe pump. At the end of this addition, the reaction mixture was of a thick, cloudy orange consistency. It was then stirred for 40 minutes and charged with another 2.7 ml of sodium methoxide in methanol over a period of 30 minutes while distilling over methanol. At the end of the addition, the solution was very thick, and another 5 ml of dimethylcarbonate was added to improve the stirring capabilities. The solution was then removed from the heat, cooled to room temperature, and allowed to set for one hour. After this time, it was reheated to reflux temperature, and another 1.1 ml of sodium methoxide in methanol was charged over a period of 13 minutes. Fifteen minutes after the addition, the heat was removed, and the solution cooled to room temperature. The solution was then stripped to remove dimethyl carbonate and then mixed with 50 ml of ethyl acetate, 50 ml of ice water and 5 ml of acetic acid. The resulting mixture was shaken and separated and the organic phase was washed with 50 ml of water, and dried over magnesium sulfate. The solution was then filtered and stripped on an aspirator, yielding 5.75 g of a dark brown oil which was identified as being the subject compound by suitable analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CC#N>[Br:12][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH2:9])[C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Nc1cccc(Br)c1N
Temperature: 70 °C
Reaction time: 14 h
Yield: 119.9 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (2.0 g, 11.59 mmol) and 1-bromopyrrolidine-2,5-dione (2.3 g, 12.75 mmol) in MeCN (30 mL) was stirred at 70° C. for 14 h. The reaction mixture was poured into water (100 mL) and stirred at RT for 1 h. The precipitate was filtered and washed with water. The solid was dried under vacuum to afford 3-bromobenzene-1,2-diamine as a yellow solid (2.6 g, 86.7%).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CS(C)=O>[C:21]1([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH2:2][O:38][CH2:37][CH2:36][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:5])=[O:4])[CH2:11][CH2:10]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCN1CCCCC1
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCOCCN4CCCCC4)CC3)c[nH]c12
Temperature: 80 °C
Yield: 44.6 %

Procedure:
The mixture of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (21 mg, 0.05 mmol) in DMSO (1.0 mL), were added 2-(1-piperidinyl)ethanol (64.6 mg, 0.5 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg). The reaction solution was heated to 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (12.0 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][CH3:23].Cl>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:17][C@@H:16]([CH3:20])[N:15]([CH2:21][CH2:22][CH3:23])[C@@H:14]([CH3:13])[CH2:19]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Agent: Cl
Product: CCCN1[C@H](C)CN(c2ccc(Cl)c(C(F)(F)F)c2)C[C@@H]1C

Procedure:
Beginning with 5-bromo-2-chlorobenzotrifluoride and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 256° C. (HCl), MS m/z (rel. intensity, 70 eV)) 335 (M+, 5), 305 (55), 112 (bp), 70 (67), 56 (82).
Reaction SMILES: [C:1]1([C@H:7]([NH2:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[BH4-].[Na+].[ClH:28]>C(O)C>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:16][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:20][CH:19]=1.[ClH:28]
Reactant: Cc1ccc(C[C@@H](N)c2ccccc2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C[C@@H](NCc2ccc(O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
21.13 g (0.1 mole) of (R)-(-)-α-phenyl-β-p-tolylethylamine (optical purity: 100%) and 12.82 g (0.105 mole) of p-hydroxybenzaldehyde were dissolved in 750 ml of ethyl alcohol. The reaction solution thus obtained was stirred at room temperature for 3 hours, and then stirred under reflux for 1 hour. Thereafter, the reaction solution was admixed at room temperature with 1.89 g (0.05 mole) of sodium borohydride, stirred for 3 hours, and then stirred under reflux for 1 hour. The reaction mixture was admixed with 75 ml of a 10% hydrochloric acid, and then concentrated under reduced pressure to give a crude (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine·HCl salt, which was thereafter neutralized with an aqueous sodium hydroxide solution. The resultant solution was concentrated under reduced pressure to obtain the crystals, which were then recrystallized from ethyl alcohol, so that 20.47 g of (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine were obtained as colorless crystals. Yield: 64.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([OH:19])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(CC(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
187 mg (500 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 770 μl (10.0 mmol) of TFA were reacted according to General Method 6A. Yield: 159 mg (93% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]([NH:37]O)([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:37][CH:34]([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)NO
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 46.5 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-][1]benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-isopropylhydroxylamine hydrochloride (345 mg, 3.09 mmol) was added and the solution was stirred for 55 minutes at room temperature. To the resulting solution was added water (40 mL) giving a precipitate which was separated bv filtration. This crude product was purified by flash chromatography eluting with chloroform:2-propanol (98:2-96.5:3.5) to give the title compound (167 mg, 47% yield, m.p. 224° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li]CCCC.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][CH2:17][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: O=C1Cc2ccccc2N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1CCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 4914.3 %

Procedure:
To a suspension of 1,3-dihydroindol-2-one (13.3 g, 0.10 mol) in THF (350 mL) was added dropwise n-BuLi (2.5 M in hexane, 84.0 mL, 0.21 mol) at 0° C. under nitrogen atmosphere. After stirring for 1 h at 0° C., the reaction mixture was cooled to −70° C. and a solution of 1-(2-bromo-ethoxy)-2,4-dichlorobenzene (32.4 g, 0.12 mmol) in THF (100 mL) was added dropwise. The mixture was stirred overnight at r.t and poured into NH4Cl (aq. sat.). The separated aqueous layer was extracted with EtOAc three times. The combined extracts were washed with water, dried and evaporated. The crude product was purified by silica gel chromatography first and then purified by prep HPLC to give 3-[2-(2,4-dichlorophenoxy)-ethyl]-1,3-dihydroindol-2-one (1.9 g, 5.8% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 10.38 (s, 1H), 7.54 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.28 (1H, J=7.2 Hz), 7.17-7.13 (m, 2H), 6.92 (t, 1H, J=7.2 Hz), 6.81 (d, 1H, J=7.6 Hz), 4.24-4.20 (m, 2H), 3.59 (t, 1H, J=6.8 Hz), 2.29-2.19 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][N:8]([CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1
Reactant: CCn1nccc1-c1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-(2-ethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in N,N-dimethylforamide at 4° C. To the solution was added sodium hydride in small portions. The flask was warmed to room temperature and stirred for 1 hour. To the mixture was added chloromethyl pivalate. The reaction mixture was stirred for 2 hours at room temperature, and quenched with methanol. Saturated ammonium chloride solution was added, and the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, and the organic layer was washed four times with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in acetone. The insoluble residue remaining was filtered off and discarded. The filtrate was concentrated in vacuo and the crude material re-crystallized to afford 2,2-dimethyl-propionic acid 5-bromo-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 405.3+407.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([CH:22]=[CH2:23])[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:26]1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CO>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([O:21][CH3:26])=[O:20])[CH:16]=[C:15]([CH:22]=[CH2:23])[N:14]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 93.7 %

Procedure:
2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23) (580 mg, 1.73 mmol), HOBt (279.5 mg, 2.07 mmol), and EDC (395.4 mg, 2.07 mmol) in dry dichloromethane were stirred for 20 minutes at room temperature and MeOH (3.46 mL, 86.5 mmol) was added thereto. After the reaction was complete, the solvent was removed in vacuo. The residue was dissolved in dichloromethane which was then washed with H2O. The organic layer was dried over anhydrous MgSO4 and concentrated to give oily residue. The resulting oil was purified by Combiflash (50% EtOAc in Hexanes) to give methyl 2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate (24) (568 mg, 94% yield). 1H NMR (400 MHz, CD3OD): 8.45 (2H, d, J=8.5 Hz), 7.74 (1H, s), 6.90-7.01 (6H, m), 6.77-6.86 (1H, dd, J=11, 18 Hz), 6.60 (1H, d, J=17 Hz), 5.7 (1H, d, J=10.5 Hz), 3.98 (3H, s); LC/MS: m/z=351[M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[C:51]([O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:61](=[NH:64])[CH2:62][SH:63])[CH2:57][CH2:56]1)(=[O:53])[NH2:52]>C(#N)C.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd]>[C:51]([O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:61](=[NH:64])[CH2:62][S:63][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:57][CH2:56]1)(=[O:53])[NH2:52]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: N=C(CS)N1CCC(OC(N)=O)CC1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCC(OC(N)=O)CC3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
1.83 ml of diisopropylethylamine and 2.18 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 3.48 g of 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 20 ml of anhydrous acetonitrile, and the mixture was stirred for one hour with ice-cooling. The reaction mixture was then added to a mixture of 2.1 ml of diisopropylethylamine in 70 ml of tetrahydrofuran and 60 ml of 0.1M phosphate buffer solution (pH 7.0), which had been cooled with ice and salt, together with 10 ml of an aqueous solution of 3.17 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylmercaptan hydrochloride, and the resulting mixture was stirred for 5 minutes. The reaction mixture was then subjected to hydrogenation at room temperature for 2 hours, in the presence of 3.0 g of 10% palladium-carbon. The hydrogenated reaction mixture was worked up in the same manner as in Example 1(3), giving 783 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][C:25](OC)=[N:24]2)=[CH:19][CH:18]=1>C(O)(C)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[N:24]=[C:25]([NH:15][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:26][CH2:27]2)=[CH:21][CH:22]=1
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: COC1=NC(c2ccc(Br)cc2)CC1
Solvent: CC(C)O
Product: Brc1ccc(C2CCC(NC(Cc3ccccc3)c3ccccc3)=N2)cc1
Yield: 55.3 %

Procedure:
A solution of 1,2-diphenyl-ethylamine (500 mg, 2.5 mmol) and 2-(4-bromo-phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (770 mg, 3.04 mmol) in isopropanol (3 mL) was stirred at 150° C. for 1 h under microwave irradiation (300 W). The resulting suspension was concentrated under reduced pressure. Flash column chromatography purification (NH2-modified SiO2, gradient of cyclohexane/ethyl acetate) of the residue yielded 580 mg (55%) of the desired product as a colorless solid.