Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[Cl-].[CH3:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]2[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:9]2[N:8]=1.C(N(CC)CC)C>ClCCl.O>[CH3:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]2[N:17]=[C:18]([CH:20]=[O:21])[N:19]=[C:9]2[N:8]=1
Reactant: Cc1nc2nc(CO)nn2c2c1CCCC2
Agent: [Cl-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2nc(C=O)nn2c2c1CCCC2
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a round bottomed flask was loaded 1 ml of DMSO and 5 ml dichloromethane. The mixture was cooled to −50˜−60° C. Then a mixture of 1 ml oxallyl chloride and 2 ml dichloromethane was injected in into the flask all at once. The mixture was stirred at the same temperature for another 5 minutes. Then 0.218 grams of (5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-methanol in 2 ml dichloromethane was added within 2 minutes. The mixture was stirred at −50˜−60° C. for fifteen minutes and 0.7 ml triethylamine was next added. After another five minutes the reaction media was warmed up to 23° C. and a mixture of 20 ml water and 200 ml dichloromethane was added. The organic layer was dried over magnesium sulfate. Filter off the drying agent and concentrate the filtrate yielded 0.216 grams of product (99%). MS: 217.1 (M+H). H-NMR (CDCl3): δ 10.20 (s, 1H), 3.23 (m, 2H), 2.78 (m, 2H) 2.63 (s, 3H, CH3), 2.00 (m, 4H),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[C:17]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][C:11]=2[C:12](OC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[N:45]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][N:46]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[C:17]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:16][C:11]=2[C:12]([NH:51][C:48]2[CH:49]=[CH:50][N:45]=[N:46][CH:47]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: Nc1ccnnc1
Reactant: COC(=O)c1cc(CN2CCOCC2)c(-c2cnn(C)c2)cc1OCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cn1cc(-c2cc(OCc3ccc(F)cc3)c(C(=O)Nc3ccnnc3)cc2CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-4-(1-methyl-1H-pyrazol-4-yl)-5-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 18; 144 mg, 0.33 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (23.54 mg, 0.98 mmol) and water (1 ml). The mixture was stirred at room temperature for 18 hours then neutralised with 2M hydrochloric acid (0.79 ml, 1.59 mmol). The solvent was removed in vacuo and the residue redissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.11 m, 0.66 mmol), 4-pyridazinamine (40.5 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (53.5 mg, 0.39 mmol) and EDC (94 mg, 0.49 mmol) were added and the solution was stirred for 3 hours. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 57 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl.[OH-].[Na+].Br.[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30]Br)[N:25]=2)[N:20]=1>CC(N(C)C)=O>[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30][NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:7]=3)[N:25]=2)[N:20]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: CC(=O)NCCc1ccc(N)cc1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)NCCc1ccc(NCc2cnc3nc(N)nc(N)c3n2)cc1
Reaction time: 48 h
Yield: 70 %

Procedure:
A solution of N-[2-(4-aminophenyl)ethyl]acetamide (713 mg, 4 mmoles) and I (672 mg, 2 mmoles) in DMAC (8 ml) was stirred under N2 at about 25° in a stoppered flask protected from light for 2 days. The precipitate was isolated by filtration and the solid on the funnel was washed with DMAC (2 × 4 ml). The filtrate was set aside, and the solid was then washed with EtOH (5 ml) and H2O (2 × 3 ml). The addition of an equal volume of H2O to the DMAC filtrate afforded more product which was isolated by filtration and washed with H2O. Evaporation of the EtOH-H2O washes also afforded more product, which was triturated with Et2O and isolated by filtration. The combined yield was 70% (609 mg). A sample obtained in this manner was recrystallized from MeOH to give the pure product in about 50% recovery. Anal. Calcd for C17H20N8O.HBr.2H2O: C, 43.50; H, 5.37; N, 23.88. Found: C, 43 .40; H, 5.42; N, 23.82. Spectral data: λ max, nm (ε × 10-3), 0.1 N HCl, 246 (17.9), 292 (5.80), 337 (10.2), 347 (sh); pH 7, 257 (27.6), 280 (sh), 372 (7.70); 0.1 N NaOH, 257 (28.6), 280 (sh), 372 (7.96); pmr (DMSO-d6), δ 1.76 (s, 3, CH3), 2.56 (m, 2, C6H4 --CH 2 CH2), 3.16 (m, 2, CH2NHCO), 4.52 (s, 2, CH2NHC6H4), 6.80 (m, 4, C6H4), 8.84 (s, 1, C7 --H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1(Cl)[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]1(Cl)[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: ClCCCOC1(Cl)C(Cl)=CC=CC1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1
Yield: 27.7 %

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-1,2-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white crystalline solid, m.p. 101.5°-103° C. was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[N:51]1([CH2:57][C:58]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:59])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:54]3[CH2:53][CH2:52][N:51]([CH2:57][C:58](=[O:59])[N:60]4[CH2:61][CH2:62][CH2:63][CH2:64]4)[CH2:56][CH2:55]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCCC1
Yield: 58.9 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.14 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.25 mL, 2.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (305 mg, 1.59 mmol), 1-hydroxybenzotriazole monohydrate (200 mg, 1.48 mmol) and 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (337 mg, 1.71 mmol) in a similar manner to Step 7 of example 1, was triturated in mixed solvent of ethyl acetate/methanol to obtain Compound 121 (298 mg, 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:26]3[O:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:25]1[C:26]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:23][CH2:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
The mixture of 2-[(2,3-Dihydro-benzofuran-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (39) (250 mg, 0.71 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (40) as white solid (200 mg, 87%).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([Si:26]([CH3:57])([CH3:56])[O:27][C:28]1[CH:55]=[CH:54][C:31]2[C:32]3[CH:41](O)[O:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:38]=4)[C:33]=3[CH2:51][CH2:52][O:53][C:30]=2[CH:29]=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.C1(C)C=CC=CC=1.Cl.CCOC(C)=O>[C:22]([Si:26]([CH3:56])([CH3:57])[O:27][C:28]1[CH:55]=[CH:54][C:31]2[C:32]3[CH:41]([C:2]4[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]5)=[CH:4][CH:3]=4)[O:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:43][Si:44]([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46])[CH:38]=4)[C:33]=3[CH2:51][CH2:52][O:53][C:30]=2[CH:29]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(O)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine (150 mg, 0.453 mmol) was dissolved in THF and cooled to −78° C. To the reaction mixture was then added n-butyl lithium (2M solution in pentane, 226 μl), slowly over 5 min. The reaction mixture was stirred for 1 h at −78° C. In a separate flask, 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol (28 mg, 0.053 mmol)) was dissolved in THF (1 mL) and added to the reaction mixture containing the 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine and n-butyl lithium, slowly over 5 min. The reaction mixture was stirred for additional 1 hr. The reaction mixture was quenched by MeOH (0.5 mL), treated with a saturated solution of ammonium chloride (30 mL) and then diluted with diethyl ether (25 mL). The organic layer was separated and washed with brine (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to yield a crude oil. The crude oil was diluted with toluene (30 mL) and 1 N HCl (6.0 mL) and then stirred for 30 min at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed twice with water (20 ml) and with a saturated solution of NaHCO3 (10 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered and evaporated to yield 1-(2-{4-[2,8-Bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)piperidine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH:31]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:32][CH:33]([OH:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:31]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:32][CH:33]([OH:35])[CH3:34])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)CNCC(C)O
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(CC(C)O)CC(C)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:22])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(Cl)c2Cl)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-(2,3-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (3.0 g, 8.7 mmol), methylen chloride (50 ml), trifluoroacetic acid (10 ml). Yield: 0.88 g. MS m/z (rel. intensity, 70 eV) 246 (M+, 8), 245 (14), 212 (34), 210 (bp), 192 (67).
Reaction SMILES: [CH3:1][N:2]1[C:20](=O)[C:19](=O)[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[CH3:1][N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3ccccc3Cc3ncccc3N2C(=O)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN2c3cccnc3Cc3ccccc3C2C1
Temperature: 15 °C

Procedure:
1.46 g (0.005 mol) 2-methyl-3,4-dioxo-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[2,3-f]azepine is added cautiously to a suspension of 0.4 g LiAlH4 in 25 ml dry dioxan under nitrogen at 25° C. The reaction mixture is boiled under reflux for 2 hours, after which it is cooled to 15° C. 5 ml water is then added, and the inorganic salts are filtered off and rinsed with dioxan. The filtrate is evaporated to dryness, giving a yellow oil. Melting point maleate salt: 163°-164° C (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]([NH2:24])=[O:23].[I-].[K+].C(N(C(C)C)CC)(C)C.CNC(=O)CCl.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu](I)I.O1CCOCC1>[O:23]=[C:22]1[CH2:21][N:9]2[C@H:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C@H:7]3[C:6]3[C:10]2=[C:2]([CH:3]=[CH:4][CH:5]=3)[NH:24]1
Reactant: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Reactant: NC(=O)CCl
Agent: I[Cu]I
Agent: CNC(=O)CCl
Agent: CNCCNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Temperature: 103 °C

Procedure:
Alternative to Example 5 above, (6bR,10aS)-ethyl 3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate may also be made in a one pot method starting from Compound of Formula 1D. A 2 liter 4 neck round bottom flask is equipped with a mechanical stirrer, reflux condenser, N2 inlet, teflon covered K-type temperature probe with a controller, and a heating mantle. To the flask is charged (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), chloroacetamide (124 g, 1153 mmol, 1.5 equiv), potassium iodide (191.5 g, 1160 mmol, 1.5 equiv), diisopropyl ethylamine (266 mL, 1531 mmol, 2.0 equiv), and dioxane (625 mL). The reaction is heated to reflux temperature of about 103° C. until less than 3% of the starting substrate is observed by HPLC (about 48 hours). Additional charge of N-methyl chloroacetamide and diisopropyl ethylamine maybe necessary. The reaction is then cooled to ca. 80° C., and at this temperature copper iodide (29.2 g, 153.8 mmol, 0.2 equiv), potassium carbonate (232.5 g, 1682 mmol, 2.2 equiv), dimethylethylene diamine (49.6 mL, 461 mmol, 0.6 equiv), and additional dioxane (375 mL) is added. The reaction is then re-heated to reflux and is monitored by HPLC. Reflux occurs at ca. 103° C. The reaction is monitored by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])[C:18]([Cl:36])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: C#CCNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: C#CCNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.037 g, 0.00021 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-prop-2-ynyl-benzamide (0.069 g, 0.00019 mol), and 10-Camphorsulfonic acid (0.0045 g, 0.000019 mol), in Isopropyl alcohol (1 mL) was microwaved at 120° C. for 30 minutes. Sodium bicarbonate was added to the reaction mixture, which was then filtered and the resulting ppt was washed first with water then three times with 1 mL of Isopropyl alcohol. 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3,5-difluoro-N-prop-2-ynyl-benzamide was isolated as tan solids (49 mg, 51%). MP: 194° C.; LCMS: 497 (M+H); 1HNMR (DMSO): 9.33 (s, 1H), 9.27 (s, 1H), 8.93 (d, J=5.64 Hz, 1H), 8.87 (s, 1H), 8.14 (s, 1H), 7.57 (t, J=8.84 Hz, 1H), 7.34 (d, J=8.60 Hz, 1H), 7.19 (d, J=9.36 Hz, 1H), 7.09 (s, 1H), 6.93 (d, J=7.56 Hz, 1H), 3.99 (s, 2H), 3.11 (s, 1H), 2.57 (t, J=5.52 Hz, 2H), 2.08 (d, J=5.56 Hz, 2H), 2.03 (t, J=6.80 Hz, 2H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[N:12]([CH2:22][C:23]([O:25]CC)=[O:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([S:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:12]([CH2:22][C:23]([OH:25])=[O:24])[C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cn1c(SCc2ccncc2)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCc3ccncc3)n(CC(=O)O)c2-c2ccc(OC)cc2)cc1

Procedure:
Starting substances: 584 mg (1.2 mmol) of Z25 from Example 124; 5 ml (10 mmol) of 2 N NaOH
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[N:47]=[C:20]2[CH:21]=[CH:22][C:23]([O:25][C:26]3[CH:27]=[C:28]([NH:33][C:34](=[O:46])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([C:44]#[N:45])([CH3:43])[CH3:42])[CH:36]=4)[CH:29]=[CH:30][C:31]=3[CH3:32])=[CH:24][N:19]2[N:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:44]([C:41]([C:37]1[CH:36]=[C:35]([C:34]([NH:33][C:28]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH:27]=2)[O:25][C:23]2[CH:22]=[CH:21][C:20]3[N:19]([N:18]=[C:17]([NH:16][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:9])[N:47]=3)[CH:24]=2)=[O:46])[CH:40]=[CH:39][CH:38]=1)([CH3:43])[CH3:42])#[N:45]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Reactant: O=C(O)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3ccccn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a solution of pyridine-2-carboxylic acid (234 mg, 1.90 mmol) in tetrahydrofuran (6 mL) were added oxalyl chloride (206 μL, 2.38 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (203 mg, 0.475 mmol) were dissolved in pyridine (7 mL), and the mixture was stirred at room temperature for 23 hr. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=40/60→20/80), and fractions containing the desired product were concentrated under reduced pressure. The crystals precipitated during concentration were collected by filtration and dried to give the title compound (146 mg, 58%) as colorless crystals.
Reaction SMILES: CC1C=C2[C:9](=CC=1[N+]([O-])=O)[NH:8][CH2:7]CC2.C([O-])([O-])=O.[K+].[K+].BrCC(Cl)=O.Br[CH2:27][C:28]([N:30]1[C:39]2[C:34](=[CH:35][C:36]([CH3:43])=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29].N(C)C>C1COCC1.O.CCOC(C)=O>[CH3:7][N:8]([CH3:9])[CH2:27][C:28]([N:30]1[C:39]2[C:34](=[CH:35][C:36]([CH3:43])=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29]
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NCCC2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2
Agent: CNC
Agent: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a bright orange solution of 6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (2 g, 10.41 mmol)—(see Achvlediani, R.; Natsvlishvili, M.; Baberkina, E.; Khachidze, M.; Abesadze, I.; Suvorov, N. Synthesis of 1H-pyrrolo[3,2-g]- and 1H-pyrrolo[2,3-g]quinoline. Izvestiya Akademii Nauk Gruzii, Seriya Khimicheskaya (1996), 22(1-4), 43-47.)—in THF (50 mL) was added K2CO3 (4.31 g, 31.2 mmol). The resulting mixture was cooled to 0° C. and was treated with bromoacetyl chloride (1.040 mL, 12.49 mmol) dropwise. The reaction mixture was stirred for 20 min. EtOAc (100 mL) and water (100 mL) were then added. The organic layer was dried (Na2SO4) and concentrated. The crude 1-(bromoacetyl)-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (3.26 g, 10.41 mmol) was dissolved in THF (50mL). A 2M Me2NH solution in THF (50 mL) was added. The resulting slurry was filtered, the solids were rinsed with THF. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford as a yellow solid (2.09 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.97 (m, 2H), 2.24 (s, 6H), 2.47 (s, 3H), 2.80 (t, J=6.89 Hz, 2H), 3.25 (s, 2H), 3.68-6.85 (m, 2H), 7.29 (s, 1H), 8.54 (br s, 1H); ESIMS (M+H)+=278.40.