Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]3[O:17][CH2:18][O:19][C:14]3=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.C1CCC(C(O)=O)CC=1.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>O>[CH2:18]1[O:17][C:15]2=[CH:16][C:4]3[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=3[CH:13]=[C:14]2[O:19]1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Brc1oc2cc3c(cc2c1-c1ccccc1)OCO3
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1oc2cc3c(cc2c1-c1ccccc1)OCO3

Procedure:
To a solution of 5.2 g. (0.016 mole) of 2-bromo-5,6-methylenedioxy-3-phenylbenzofuran in 225 ml. of acetic acid is added with stirring 5.0 g. (0.024 mole) of cyclohexene-4-carboxylic acid, then 2.2 g. (0.024 mole) of dinitrogen tetraoxide in 25 ml. of acetic acid. After about one hour the mixture is poured into cold water, and the yellow product is collected and washed with water. The product is dissolved in dichloromethane, and the solution is washed with cold 5 percent sodium hydroxide solution, water and saturated sodium chloride solution, then dried. The solution is concentrated to dryness to provide a yellow residue which is recrystallized from a benzene-hexane mixture, then from an isopropanol-benzene mixture to provide yellow needles of 5,6-methylenedioxy-2-nitro-3-phenylbenzofuran, m.p. 180°-183° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Pd]
Product: NCCCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The starting materials were D-glucose and L-(+)-lysine in the molar ratio 1:1. The reductive amination took place using palladium/activated carbon (10%) as a catalyst under the conditions of the above examples and yielded a colorless, wax-like product.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3CCCC[O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25](O)[CH2:26][CH:27]([CH3:29])[CH3:28]>C(O)=O.[Zn]>[CH:15]([O:14][CH2:13][CH2:12][CH2:11][N:8]1[C:9](=[O:10])[C:4]2[C:3]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:2]([Br:1])[CH:24]=[N:23][C:5]=2[N:6]([CH3:22])[C:7]1=[O:21])=[O:16]
Reactant: CC(C)CC(O)c1c(Br)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)CCc1c(Br)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 55.4 %

Procedure:
To a solution of 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (85 mg, 0.175 mmol) in HCOOH (1 mL) was added Zn dust (57 mg, 0.877 mmol). The reaction was heated at 50° C. for 2 h then cooled to RT and filtered. The filtrate was concentrated to give 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 47.0% yield) as a white solid. LCMS: MH+ 412 and TR=2.076 min. Used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (75 mg, 0.21 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (42 mg, 1.05 mmol, 4.94 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aqueous hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 80% in 8 min, up to 100% in 1.5 min); Detector, uv 220&254 nm. This resulted in 20 mg (27%) of 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: CS(C)=O.[OH:5][CH:6]1[CH2:28][CH2:27][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(Cl)(=O)C(Cl)=O.Cl>ClCCl.C(N(CC)CC)C>[F:26][C:23]([F:24])([F:25])[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:8][CH2:7][C:6](=[O:5])[CH2:28][CH2:27]3)[C:13]2=[O:14])=[CH:20][CH:19]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCC(O)CC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)nc1)C2=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
DMSO (5.19 mL) was added dropwise over a period of 5 minutes to a solution of 8-hydroxy-2-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (9.53 g, obtained in example 108, step 3) in dichloromethane (100 mL) that was cooled down to −78° C. in a CO2/acetone-bath. After 5 minutes, oxalylchloride (3.04 mL) was added dropwise over a period of 10 minutes and stirring was continued for 30 minutes at −78° C. Then, triethylamine (17 mL) was added dropwise over a period of 10 minutes to the reaction mixture and after 5 minutes, the mixture was allowed to warm to 20° C. The reaction mixture was poured into ice/water and was acidified with 2M aqueous HCl solution (150 mL) to pH 3. The aqueous phase was extracted two times with dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of dichloromethane in acetonitrile) to give the title compound as a light yellow solid (6.19 g, 80%). MS (m/e): 343.2 [MH+].
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].Br[C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45](S(C2C=CC=CC=2)(=O)=O)[C:44]=1[CH2:61][O:62][CH3:63].[OH-].[Na+]>O1CCOCC1.C(O)C.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>[CH3:63][O:62][CH2:61][C:44]1[NH:45][C:46]2[C:51]([C:43]=1[C:18]1[N:19]=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:21]3[S:22][C:14]([CH2:13][N:10]4[CH2:11][CH2:12][N:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4])[CH2:8][CH2:9]4)=[CH:15][C:16]=3[N:17]=1)=[CH:50][CH:49]=[CH:48][CH:47]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: COCc1c(Br)c2ccccc2n1S(=O)(=O)c1ccccc1
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
Solvent: CCO
Product: COCc1[nH]c2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Temperature: 65 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a degassed mixture of 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide (150 mg, 0.22 mmol), 3-bromo-2-(methoxymethyl)-1-(phenylsulfonyl)-1H-indole (82 mg, 0.22 mmol), copper(I) thiophene-2-carboxylate (41 mg, 0.22 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (12 mg, 0.011 mmol). The reaction mixture was reacted in the microwave at 140° C. for 35 min. The reaction mixture was filtered through paper and concentrated. The crude product was purified by flash chromatography (20% MeOH in DCM) to give a yellow paste which was dissolved in dioxane (5 mL) and ethanol (1 mL). A 12 M aqueous solution of NaOH was then added. The resulting mixture was then stirred at 65° C. for 15 hours. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 126 (12.4 mg, 10.2%). LCMS: M+H+=564.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.55 (m, 1H), 7.44 (m, 1H), 7.35 (s, 1H), 7.10 (m, 2H), 7.05 (m, 1H), 6.93 (m, 1H), 5.19 (s, 2H), 3.90 (m, 4H), 3.83 (m, 6H), 3.47 (s, 3H), 2.42-2.58 (m, 8H), 1.08 (s, 6H)
Reaction SMILES: NC1C=CC(P(=O)(OC(C)C)OC(C)C)=CC=1.[CH3:18][C:19]1([CH3:35])[CH2:24][O:23][P:22](=[O:34])([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=2)[O:21][CH2:20]1>>[CH3:18][C:19]1([CH3:35])[CH2:20][O:21][P:22]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[NH2:31])(=[O:34])[O:23][CH2:24]1
Reactant: CC1(C)COP(=O)(c2cccc([N+](=O)[O-])c2)OC1
Agent: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Product: CC1(C)COP(=O)(c2cccc(N)c2)OC1
Yield: 63 %

Procedure:
Prepared according to the procedure described for dipropan-2-yl (4-aminophenyl)phosphonate using 5,5-dimethyl-2-(3-nitrophenyl)-1,3,2-dioxaphosphinane 2-oxide. Yield: 63%. 1H-NMR (DMSO-d6, 400 MHz): δ=0.94 (s, 3 H), 1.07 (s, 3 H), 3.84 (dd, J=9.6, 10.8 Hz, 2 H), 4.07 (dd, J=11.2, 14.0 Hz, 2 H), 5.43 (s, br, 2 H), 6.75-6.78 (m, 2 H), 6.88 (d, 1 H), 7.16 (m, 1 H). MS: m/z 242.11 [MH+].
Reaction SMILES: [Cl-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15](O)=[O:16])[CH:8]=[CH:7]2>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15]([Cl:1])=[O:16])[CH:8]=[CH:7]2
Reactant: [Cl-]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reaction time: 2 h

Procedure:
2.85 ml, 32.5 mmol Oxaly chloride ((COCl)2) is added slowly to 3 g, 13 mmol (S)-2-(6-methoxy-2-naphthyl)propionic acid dissolved in 3 ml dichloromethane (CH2Cl2), and the resulting solution is heated under a first reflux temperature with stirring for 2 hours. The excess oxaly chloride is removed by evaporation under reduced pressure to obtain a crude product of (S)-2-(6-methoxy-2-naphthyl)propionic acid chloride. The crude (S)-2-(6-methoxy-2-naphthyl)propionic acid chloride is dissolved in 5 ml dichloromethane and then added to a solution of 3.36 ml, 32.5 mmol N,N′-diethylamine (HN(CH2CH3)2) and 5 ml triethylamine (TEA) in 10 ml dichloromethane with stirring under ice bath, i.e. under a temperature about 0° C. After some solids are produced, the mixture is stayed in a refrigerator overnight, i.e. stayed in a low temperature about−5° C. for a period of time about 12 hour. The mixture is evaporated to dryness under reduced pressure and the residue is purified by column chromatography over silica gel (70˜230 mesh ASTM) using dichloromethane/ethyl acetate (V:V=8:2) as the eluant. As a result, about 70 percent yield of white N,N′-diethyl (S)-2-(6-methoxy-2-naphthyl)propionate is obtained, which is the first intermediate (I) for synthesizing the chiral compound of the first preferred embodiment of the present invention.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](B(O)O)=[CH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:37]([N:38]=2)=[CH:36][CH:35]=[C:34](Cl)[N:33]=3)=[C:26]([F:40])[CH:25]=1>O1CCOCC1.O.C(Cl)Cl.CC(=O)OCC.[Pd](Cl)Cl.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[O:20]1[CH2:21][CH2:22][CH2:23][O:18][CH:19]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]3[C:37]([N:38]=2)=[CH:36][CH:35]=[C:34]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH2:14])[N:33]=3)=[C:26]([F:40])[CH:25]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Reactant: C=C(B(O)O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine) palladium dichloride (0.252 g, 0.356 mmol), potassium carbonate (6.70 g, 48.5 mmol), 1-phenylvinylboronic acid (4.64 g, 31.4 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine (5.00 g, 14.3 mmol) in 50 mL dioxane and 15 mL water was sealed and heated to 80° C. overnight. The reaction was cooled, diluted with DCM, water, and the aq. Layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown semi-solid. The solid was suspended in 100 mL EA, heated to 75° C., and filtered, rinsing with a small volume of hot EA. The filtrate was allowed to stand overnight, resulting in crystals, and was placed in the freezer overnight. The resulting crystals were collected by filtration, rinsing with a small volume of cold EA to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)-thiazolo[5,4-b]pyridine as light brown crystals. MS (ESI) m/z: Calculated: 418.1; Observed: 419.0 (M++1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:14])[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[Br-].[Li+].[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([O:35][CH2:36][CH2:37][CH2:38]I)[CH:33]=[CH:34][C:20]1=2)[CH3:18]>CN(C=O)C>[Br:3][C:4]1[C:5](=[O:14])[N:6]([CH2:38][CH2:37][CH2:36][O:35][C:32]2[CH:33]=[CH:34][C:20]3[N:19]([CH2:17][CH3:18])[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=3[CH:31]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=c1[nH]c2ccccc2cc1Br
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(Br)cc4ccccc43)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
Under ice cooling, sodium hydride (60% in oil, 0.2 g) was added to a DMF solution(10 ml) of 3-bromo-1H-quinoline-2-one(1.0 g). The mixture was stirred at the same temperature for 15 minutes. Lithium bromide(0.76 g) was added to the mixture, and the liquid was stirred at the same temperature for another 15 minutes, and then at room temperature for an hour. The reaction mixture was cooled to 0° C., and 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(2.1 g) was added thereto. The mixture was stirred at room temperature for 2 hours, and at 50° C. for 8 hours. The reaction mixture was poured to ice water, and the generated insoluble matter was separated. The insoluble matter was dissolved in a mixed solvent of ethyl acetate and dichloromethane. The liquid was dried with sodium sulfate and condensed under reduced pressure. Ethyl acetate was added to the residue. The generated insoluble matter was separated and dried to give the title compound(1.2 g) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([C:18]#[N:19])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:18]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 ml) was added at RT TMSCN (4 ml), and the solution was stirred for 5 min at RT. Then, dimethylcarbamoyl chloride (2.8 ml) was added at RT, and the resulting solution was stirred at RT for 48 h. To the reaction mixture was added a solution of aq. 10% K2CO3 (50 ml) and stirring was continued for 10 min. The phases were separated and the aq. layer extracted twice with DCM. The combined org. phases were dried over MgSO4 and evaporated off. Filtration over a plug of SiO2 (Hept/EA 8:2) gave 4.98 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]([N:11]2[C@H:18]3[C@H:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]3)[CH2:12]2)=[O:10])[O:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:18]12[N:11]([C:9]([C:8]3[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=3[C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)=[O:10])[CH2:12][C@H:13]1[CH2:14][CH2:15][NH:16][CH2:17]2
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Reaction time: 2 h

Procedure:
The product of Step B (645 mg, 1.63 mmol), DCM (8 mL), TFA (3 mL) were stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and treated with Dowex 550 A resin. After stirring for 2 h the resin was removed by filtration and the filtrate was concentrated in vacuo to a colorless oil which was taken on to the next step without further purification. MS (ESI) mass calculated for C16H18N4O2, 298.14; m/z found, 299.1.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:11]=2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of nitrile 28B (2.0 g, 5.1 mmol) in diethyl ether (40 mL) was added in small amounts to a mixture of LiAlH4 (0.39 g, 2 mol eq) in diethyl ether (50 mL) stirred at 0° C. After the addition was completed, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed at 0° C. by addition of small amount of water (40 mL), the solid formed was filtered off and the organic filtrate was separated, washed with brine (50 mL) and dried over Na2SO4. The organic phase was evaporated under reduced pressure to afford 29B as a pale orange oil (83% yield, 1.67 g, 4.2 mmol,). 1HNMR (DMSO, 400 MHz) δ 3.321 (bs, 2H), 4.01 (s, 2H), 7.50 (d, 4H, J=7.9), 7.98 (s, 2H), 8.31 (d, 4H, J=8).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:41][CH:40]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(Cl)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-chlorobenzylamine, m.p. 218-219° C. MS (+)ESI, m/z]: 576 [M+H]+ Anal. Calcd for C35H30CIN3O3: C, 72.97; H, 5.25; N, 7.29. Found: C, 72.67; H, 5.34; N, 7.11.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([Cl:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccn2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (730 mg, 2.2 mmol) and 3-chloroindole-6-carboxylic acid (468 mg, 2.4 mmol) afforded, after purification (SiO2: 10 DCM:2 EtOAc:2 Hexane:0 to 1.5 isopropyl amine), 835 mg (64%) of the title compound.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+:22].[Na]>O>[CH2:2]([N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([O-:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([O-:16])=[O:15].[Na+:22].[Na+:22].[Na+:22].[Na+:22]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]

Procedure:
A solution of tetrasodium ethylenediaminetetraacetate was prepared by mixing 8.0033 grams of solid ethylenediaminetetraacetic acid with 250 ml H2O and about 10.5 grams of a 50% aqueous solution of sodium hydroxide. This mixture includes sufficient sodium to provide a pH at least 12 (actual pH was 13.1) in the resulting solution of sodium EDTA. A large excess of caustic was avoided, because excess caustic will, in the next step of the process, react with cobalt to form cobalt hydroxide which readily oxidizes in the presence of air to the oxide. The hydroxide and the oxide form a gelatinous precipitate which can constitute a substantial cobalt loss in the process. This EDTA-solution step of the process is conducted advantageously at about 68° C.
Reaction SMILES: [I:1]I.[CH3:3][CH:4]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[I:1][C:14]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH:4]([CH3:3])[CH2:5][CH:6]([CH3:7])[CH3:8])[CH:15]=1
Reactant: II
Reactant: CC(C)CC(C)c1ccccc1N
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(C)c1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
In methanol was dissolved 2.53 g (10 mmol) of iodine, and 2-(1,3-dimethylbutyl)aniline (1.77 g, 10 mmol) was added thereto under ice-cooling, after which an aqueous solution of sodium hydrogencarbonate (1.26 g, 15 mmol) was added thereto and the resulting mixture was stirred at 0° C. for 4 hours. Sodium thiosulfate was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure, diluted with ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.71 g of the desired compound.