Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (7.0 g, 40 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (9.5 g, 40 mmols), potassium carbonate (5.5 g, 40 mmols) and N,N-dimethylformamide (100 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of tert-butyl 2-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.2 g, 96.6%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1C.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)CC>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][NH2:10])=[CH:7][N:8]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(CN)cnc1Cl
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Product: NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing (6-chloro-5-methylpyridin-3-yl)methanamine 30-4 (500 mg, 2.20 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid 33-1 (418 mg, 2.20 mmol), Pd(OAc)2 (29 mg, 0.11 mmol), S-Phos (91 mg, 0.22 mmol) and potassium phosphate (1.40 g, 6.60 mmol) under Argon was added 2-butanol (4 mL). The mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give (2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 48-1 as a dark yellow solid. MS m/z 268.1 (M+1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])([CH3:13])[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)N
Product: CC(C)NCc1cccc(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)benzonitrile and isopropyl amine. It was isolated as a yellow liquid (5.7 g, 92%). 1H NMR (DMSO-d6, 400 MHz) δ 7.73 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.49 (m, 1H), 3.56 (s, 2H), 2.75 (m, 1H), 0.83 (d, J=8.8 Hz, 6H).
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)morpholine
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN1CCN(CC(=O)N2CCC(c3ccc(NC(=O)OC(C)(C)C)cc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC(=O)N2CCC(c3ccc(N)cc3)CC2)CC1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].[C:30](O)(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg), acetic acid (13.3 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57.7 mg) and 1-hydroxybenzotriazole (40.7 mg) in anhydrous dimethylformamide (1 mL) was stirred for 3 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(1-acetyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (81.1 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:9][C:10]1[C:11]([CH3:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.[CH3:18][N:19]([CH3:36])[C:20]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C@@H:29]([CH2:33][CH2:34]Br)[NH:28][CH2:27][CH2:26]2)=[O:21].[F:37][C:38]([F:43])([F:42])[C:39]([NH2:41])=[O:40]>CN(C)C=O.O>[CH3:18][N:19]([CH3:36])[C:20]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C@@H:29]([CH2:33][CH2:34][O:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[C:11]([CH3:17])[CH:12]=1)[NH:28][CH2:27][CH2:26]2)=[O:21].[F:37][C:38]([F:43])([F:42])[C:39]([NH2:41])=[O:40]
Reactant: CN(C)C(=O)Oc1ccc2c(c1)CCN[C@@H]2CCBr
Reactant: Cc1cc(O)ccc1Cl
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC[C@H]2NCCc3cc(OC(=O)N(C)C)ccc32)ccc1Cl
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of potassium carbonate (115 mg, 0.83 mmol), potassium iodide (catalytic amount) and 4-chloro-m-cresol (65 mg, 0.46 mmol) in dimethylformamide (2 ml) was added a solution of 6-dimethylcarbamoyloxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (160 mg, 0.38 mmol) obtained in step (e) of Example 190 in dimethylformamide (2 ml) gradually with stirring under cooling in an ice bath. Subsequently, the resulting mixture was stirred at 100° C., and after confirming the disappearance of the starting material by thin layer chromatography, the reaction temperature was cooled to ambient temperature and water was added to the reaction mixture with stirring. The resulting mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (154 mg, yield: 84%) as a pale yellow oil.
Reaction SMILES: [C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C.CO>[C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12

Procedure:
A mixture of 722 mg (1.97 mmole) 1-(naphthalene-1-sulfonyl)-4-nitro-1H-indole and 100 mg 10% palladium on carbon in 15 mL ethanol and 5 mL methanol was shaken under 40 psi hydrogen at room temperature for 4 hrs. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether/hexane to provide 1-(naphthalene-1-sulfonyl) -1H-indol-4-ylamine as light yellow-green crystals, 480 mg, m.p. 133-134° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([OH:15])=O)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:25])[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[O:18]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([CH:20]1[C:21](=[O:23])[O:22][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:24])=[O:15])=[O:6])[CH:2]=[CH2:3]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C=CCOC(=O)N1CCOC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)N1CCOC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a mixture of (3S)-4-allyloxycarbonylmorpholine-3-carboxylic acid (5.20 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.5 g) in dichloromethane (50 ml) were added dicyclohexylcarbodiimide (5.00 g) and 4-dimethylaminopyridine (2.96 g), in turn, under ice-cooling. The mixture was stirred under ice-cooling for 2 hours and at ambient temperature for 18 hours. Insoluble material was filtered off. The filtrate was washed with 1N hydrochloric acid (50 ml×2) and, next, brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give 5-[(3S)-4-allyloxycarbonylmorpholin-3-yl]carbonyl-2,2-dimethyl-1,3-dioxane-4,6-dione (8.31 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19](O)[C@H:18]([F:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:18]([F:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Reactant: Oc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Cl)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-6 using 6-chloropyridin-3-ol and cis(±)tert-butyl-3-fluoro-4-hydroxypiperidine-1-carboxylate; MS: 353.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Na]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na]
Product: CC(C)(Cc1c(C(=O)Cc2ccccc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy) indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using phenylacetyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1H2O Calc. C 69.46; H 5.22; N 4.26 Found C 69.71; H 5.25; N 4.11.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[Br:14]Br>C(Cl)Cl>[Br:14][C:10]1[CH:11]=[CH:12][C:5]2[O:4][CH2:3][C:2]([CH3:13])([CH3:1])[CH2:8][O:7][C:6]=2[CH:9]=1
Reactant: CC1(C)COc2ccccc2OC1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)COc2ccc(Br)cc2OC1
Temperature: 25 °C

Procedure:
8.55 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine (see Example 10) were dissolved in 70 ml of methylene chloride (CH2Cl2) and treated at 0° C. under an Argon atmosphere with a solution of 8.0 of Br2 in 30 ml of CH2Cl2. The mixture was warmed to room temperature and left to react for 1 hour. It was then poured on to ice and extracted with ether. Washing with NaHCO3 solution and water, drying and evaporation yielded 13.35 of of 7-bromo-3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine as a colorless oil which was 94.5% pure and which contained 4.7% of starting material; it was processed in the crude state.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl-].[Li+].[CH3:16][Sn](C)(C)C>CN(C=O)C.[Cl-].[NH4+].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>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:16])[C:3]([C:12]#[N:13])=[N:4][C:5]=1[O:10][CH3:11]
Reactant: C[Sn](C)(C)C
Reactant: COc1cc(Cl)c(C#N)nc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(C)c(C#N)nc1OC
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-5,6-dimethoxypyridine-2-carbonitrile (1-6d, 1 g, 5.04 mmol) in DMF (20 mL) was added lithium chloride (2.1 g, 50.4 mmol), Pd(PPh3)4 (1.16 g, 1.0 mmol) and tetramethyltin (4.5 g, 25.2 mmol). The resulting mixture was heated at 100° C. overnight, cooled to rt, diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic layers were dried and concentrated to give a yellow oil which was purified by column chromatography (SiO2, 80 g, 0-30% EtOAc in hexane) to give 1-6e as a bone powder. ESI+ MS [M+H]+ C9H11N2O2=179.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:36]([C:35]3[CH:34]=[N:33][C:32]([Cl:31])=[CH:40][CH:39]=3)=[O:37])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)nc3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially triethylamine (0.13 ml) and 6-chloronicotinoyl chloride (107 mg, CAS 58757-38-3) and the mixture was heated at 50° C. for 4 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (177 mg, 82%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][C:5](=O)[CH2:6][O:7][C:8](=[O:10])[CH3:9].[CH3:12]S(C)=O>CCCCCC>[Cl:3][CH2:4][C:5](=[CH2:12])[CH2:6][O:7][C:8](=[O:10])[CH3:9]
Reactant: CS(C)=O
Reactant: CC(=O)OCC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=C(CCl)COC(C)=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium hydride (4.5 g.; 57% in mineral oil) is placed under a nitrogen atmosphere and the mineral oil removed with petroleum ether. Dimethylsulfoxide (30 ml.) is then added and the mixture is stirred at 70° C. for two hours and then cooled to 10° C. Methyltriphenylphosphonium bromide (35.7 g.) dissolved in dimethylsulfoxide (50 ml.) is added dropwise under nitrogen to afford a yellowish-orange ylide solution. 1-Chloro-3-acetoxy-2-propanone (15 g.) in dimethylsulfoxide (20 ml.) is then added and the reaction mixture is stirred until the color of the ylide disappears and then is stirred an additional hour at room temperature. The reaction mixture is dissolved in hexane (200 ml.) and washed three times with water. The organic phase is filtered to remove triphenylphosphine oxide and then dried over magnesium sulfate. The solvent is evaporated and the residue is distilled under vacuum to afford 1-chloro-2-methylene-3-acetoxypropane.
Reaction SMILES: [F-].[Cs+].Br[C:4]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:9]3[C:22](=[O:24])[NH:23][C:7]([C:8]=23)=[CH:6][CH:5]=1.[CH3:25][C:26]1[C:30](B(O)O)=[C:29]([CH3:34])[O:28][N:27]=1.C(O)CCC>C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl.O>[CH3:25][C:26]1[C:30]([C:4]2[C:13]3[O:12][CH2:11][CH:10]([C:14]4[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=4)[N:9]4[C:22](=[O:24])[NH:23][C:7]([C:8]=34)=[CH:6][CH:5]=2)=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: N#Cc1ncccc1C1COc2c(Br)ccc3[nH]c(=O)n1c23
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: O
Solvent: CCCCO
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C#N
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A sealed tube containing 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (11.5 mg, 0.0162 mmol), cesium fluoride (574 mg, 3.78 mmol), 3-(7-bromo-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile (386 mg, 1.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (533 mg, 3.78 mmol) was placed under vacuum and back-filled with nitrogen (repeated 3×). The sealed tube was charged with 1-butanol (4.92 mL) and water (1.2 mL) and the mixture was degassed by bubbling nitrogen for 15 min and heated at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (342 mg, 85%) as a racemic mixture. 1H NMR (300 MHz, DMSO-d6) δ 11.00 (br s, 1H), 8.81-8.66 (m, 1H), 7.80-7.62 (m, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.74-5.51 (m, 1H), 4.58 (d, J=3.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H); LCMS calculated for C20H16N5O3 (M+H)+: m/z=374.1. found: 374.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of 3-amino-2-indolecarboxylic acid ethyl ester (500 mg, 2.45 mmol) and triethylamine (272 mg, 2.70 mmol) in methylene chloride (5 mL) was added anisoyl chloride (418 mg, 2.45 mmol). The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with 1 N aqueous hydrochloric acid, dried (sodium sulfate), filtered, and concentrated in vacuo to provide a yellow solid. Recrystallization from hexane/ethyl acetate provided 780 mg (94%) of the title compound as a yellow solid.