Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:42][CH3:43])[C:7]([NH:30][CH:31]2[CH2:34][N:33]([C:35](OC(C)(C)C)=[O:36])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].F[C:45](F)(F)[C:46](O)=O>ClCCl>[C:35]([N:33]1[CH2:34][CH:31]([NH:30][C:7]2[N:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)[CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5][C:6]=2[CH2:42][CH3:43])[CH2:32]1)(=[O:36])[CH:45]=[CH2:46]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: C=CC(=O)N1CC(Nc2nc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)c(C(N)=O)nc2CC)C1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 3-{[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}azetidine-1-carboxylate (130 mg), and dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0° C., followed by stirring for 2 hours. The solvent was evaporated, and subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To a mixture of the obtained residue and chloroform (4 mL) were added diisopropylethylamine (140 μL) and acryloyl chloride (40 μL) under ice-cooling, followed by stirring at room temperature for 8 hours. The reactant was subjected to liquid separation by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-[(1-acryloylazetidin-3-yl)amino]-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (18 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([CH:23]=1)[C:14]([O:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[O:15]>C1COCC1>[Cl:5][C:6]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([CH:23]=1)[C:14]([O:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][O:20][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 765.6 %

Procedure:
Acetyl chloride (0.79 g, 0.01 mole) was added to a solution of 3-hydroxy-2,2-dimethyl-propyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (0.25 g, 0.00056 mole) and THF (10 ml). The solution was held at reflux for 3 hrs., cooled and concentrated. The residue was taken into 250 ml of ether, washed two times with water and dried over MgSO4. After the solvent was stripped off, 2.1 g of 3-Acetoxy-2,2-dimethylpropyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate was obtained as a yellowish gum, nmr (CDCl3) δ 1.0 (s, 6H), 2.03 (s, 3H), 3.87 (s, 2H), 4.12 (s, 2H), 6.96-8.22 (m, 6H); ir (CHCl3) 1743 Cm-1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH3:11])[N:10]=1)=O)C.[Br:15][CH2:16]Br.C[Li].C(O)(=O)C>C1COCC1.O>[Br:15][CH2:16][C:4]([C:6]1[N:7]([CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH3:11])[N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nc(C)nn1C(C)C
Reactant: BrCBr
Agent: [Li]C
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)CBr)n(C(C)C)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester (12.09 g, 61.3 mmol) and dibromomethane (8.63 mL, 122.6 mmol) in THF (500 mL) at −78° C. was added methyllithium (40.9 mL, 122.6 mmol, 3M solution in diethoxymethane) dropwise. The reaction mixture was stirred at −78° C. for 15 min. Acetic acid (3 mL) was added and the reaction mixture allowed to warm to RT. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 2-Bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone as a colourless oil which crystallised on standing (11.26 g, 75%). 1H NMR 400 MHz (CDCl3) δ: 5.41 (1H, sept, J=6.6 Hz), 4.67 (2H, s), 2.44 (3H, s), 1.49 (6H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([O:10]CC)=O.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([NH2:21])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.Cl>C(OCC)(=O)C.CN(C=O)C>[Cl:13][C:14]1[N:19]=[CH:18][C:17]2[NH:21][C:8](=[O:10])[C@H:3]3[C@H:2]([CH3:1])[O:7][CH2:6][CH2:5][N:4]3[C:16]=2[N:15]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)[C@@H]1NCCO[C@H]1C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1OCCN2c3nc(Cl)ncc3NC(=O)[C@@H]12
Temperature: 80 °C
Reaction time: 16 h
Yield: 22.7 %

Procedure:
A scintillation vial equipped with a magnetic stirrer was added (2S,3R)-ethyl 2-methylmorpholine-3-carboxylate (383 mg, 2.211 mmol), DMF (3 ml), 2,4-dichloropyrimidin-5-amine (363 mg, 2.211 mmol), followed by DIEA (0.386 ml, 2.211 mmol). The reaction was stirred at 80° C. for 16 hours. NaOH (2 mL, 2.5N) was added and continued heating at 110° C. for 2 hours. After cooling to room temperature Boc2O (2 eq.) was added and stirred for 16 hours. The reaction was acidified with HCl (6N) to pH of about 2. The reaction mixture was poured into ethyl acetate and washed successively with water, brine, then dried over Na2SO4, and concentrated in vacuo to give a crude oil. Crystals formed after standing for 16 hours. The crystals were filtered and washed with ether to afforded (6aR,7S)-2-chloro-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (128 mg, 0.503 mmol, 22.73% yield) as a brown solid. The mother liquor was treated with TFA to afforded a crude (2S,3R)-2-methylmorpholine-3-carboxylic acid, TFA (145 mg, 0.559 mmol, 25.3% yield) which was combined with 2,4-dichloropyrimidin-5-amine (164 mg, 1 mmol) in DMF (1 ml) and DIEA (0.524 ml, 3.00 mmol). The reaction was heated at 80° C. for 16 hours. The reaction solution was poured into ethyl acetate and successively washed with water and brine. The organic layer was dried over Na2SO4, concentrated in-vacuo to give a brown oil. The oily residue was allowed to stand for 16 hour to give a solid which was filtered and rinsed with ether to afford (6aR,7S)-2-chloro-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (77 mg, 0.302 mmol, 30.2% yield). MS [M+H] found 255.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[CH2:5]1)(=O)C.[ClH:16]>>[ClH:16].[N+:13]([C:11]1[S:10][C:7]2[CH2:8][CH2:9][NH:4][CH2:5][C:6]=2[CH:12]=1)([O-:15])=[O:14]
Reactant: CC(=O)N1CCc2sc([N+](=O)[O-])cc2C1
Agent: Cl
Product: O=[N+]([O-])c1cc2c(s1)CCNC2

Procedure:
2.38 g (10.53 mmole) of 5-acetyl-2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [prepared as described in step (b) above] were heated under reflux for 2 hours in 60 ml of 10% w/v aqueous hydrochloric acid. The reaction mixture was then concentrated to dryness by evaporation under reduced pressure, to give 2.19 g of the title compound as brown crystals.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCOCC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, morpholine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76 to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-morpholin-4-yl-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 459.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[N+:27]([C:30]1[CH:31]=[C:32]([S:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 3.9 g of (7b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 5.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Ni].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]([OH:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: O
Product: CC(O)c1cccc(N)c1
Yield: 38.7 %

Procedure:
Following the procedure of Example I m-nitroacetophenone (82.5 g., 0.50 mole; 99% purity by GLC), water (300 ml.), and Raney nickel catalyst (27 g. (wet), Grace No. 4200) charged to a 1 liter Parr stirring autoclave. The hydrogen pressure was 50 psi initially and allowed to decrease to 40 psi whereupon the pressure was raised to 50 psi and again allowed to decrease as hydrogenation continued. The temperature was slowly raised from 25° C to 100° C. After 61/2 hours, hydrogen absorption apparently ceased. Work-up as in example I gave 26.5 g. m-amino-α-methylbenzyl alcohol (38.7% yield) which was 100% pure by GLC and a residue of 38.1 g. which contained 87.2% m-amino-α-methylbenzyl alcohol and 12.8% m-aminoacetophenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.[NH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC(O)CN
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1F)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of 5-(2-fluorophenyl)-1,3-cyclohexanedione (2.0 g), 3-aminopropan-2-ol (0.95 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the solution were added 2-bromomesitylene (1.9 g), tetrakistriphenylphosphine palladium (0.28 g) and potassium carbonate (2.7 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (0.96 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:40])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([N:15]([CH3:38])[C@H:16]([C:23]3[CH:28]=[CH:27][C:26](C4C=CC=C(C(N)=O)C=4)=[CH:25][CH:24]=3)[CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:14])[C:6]=2[CH:39]=1.[NH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43]>>[Cl:1][C:2]1[C:3]([Cl:40])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([N:15]([CH3:38])[C@H:16]([C:23]3[CH:24]=[CH:25][C:26]([C:47]4[CH:48]=[CH:49][C:44]([C:42]([NH2:41])=[O:43])=[CH:45][CH:46]=4)=[CH:27][CH:28]=3)[CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:14])[C:6]=2[CH:39]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)[C@@H](CN1CCCC1)c1ccc(-c2cccc(C(N)=O)c2)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)[C@@H](CN1CCCC1)c1ccc(-c2ccc(C(N)=O)cc2)cc1

Procedure:
4′-[(1R)-1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(1-pyrrolidinyl)ethyl]-4-biphenylcarboxamide was prepared in a similar manner as in the preparation of 4′-[(1R)-1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(1-pyrrolidinyl)ethyl]-3-biphenylcarboxamide except replacing [3-(aminocarbonyl)phenyl]boronic acid with [4-(aminocarbonyl)phenyl]boronic acid. As is appreciated by those skilled in the art, this analogous example may involve variations in synthetic procedure.
Reaction SMILES: [C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([OH:12])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1n[nH]c(C(=O)O)c1Cl
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1n[nH]c(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1Cl
Yield: 30.8 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-acetyl-4-chloro-1H-pyrazole-5-carboxylic acid (0.527 g, 2.79 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.56 g, 2.148 mmol). The product was purified by reverse phase flash chromatography. Yield 30.8%. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 2.54 (s, 3H), 4.31 (dd, 1H), 4.37 (dd, 1H), 4.42-4.51 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 8.27 (bs, 1H), 14.45 (s, 1H).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>C(O)CCC>[ClH:1].[ClH:1].[N:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1
Reactant: CCOC(COc1ccncc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(COc1ccncc1)NCC2
Yield: 215.2 %

Procedure:
A mixture of 3,4-dihydroxyphenethylamine hydrochloride (2.4 g), (4-pyridyl)oxyacetaldehyde diethyl acetal (3.7 g), n-butanol (40 ml) and 1N-hydrochloric acid (20 ml) was refluxed for 15 hours under stirring. After the reaction, n-butanol was distilled off from the reaction mixture under reduced pressure. The residue was dissolved in water, and the solution was washed twice with chloroform and once with ether. The aqueous layer was concentrated, and the oily residue was allowed to stand to give crystals of 1-(4-pyridyl)oxymethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (4.7 g). The product was recrystallized from aqueous methanol to give needles, mp 250° to 255°C (dec.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([CH2:29][C:30]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH2:33]O)#[N:28]>C(Cl)Cl>[C:35]1([C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:31][CH2:32][CH2:33][I:25])[CH2:29][C:27]#[N:28])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: II
Reactant: N#CCC(CCCO)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CCC(CCCI)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of triphenylphosphine (1.68 g) in methylene chloride (30 ml) and imidazole (0.44 g) was added iodine (1.62 g). To this mixture was added a solution of 5-cyano-4,4-diphenylpentanol (1.3 g) in methylene chloride (5 ml) dropwise. After completion of dropwise addition, the mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated to dryness. To the group was added isopropyl ether, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to provide the title compound (1.5 g) as colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>Cl.[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N1CCNCC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N3CCNCC3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.85 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-1-(piperazin-1-yl)ethanone (0.135 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to gives 35 mg, and then the compound was stirred in ethanolic HCl to give the HCl salt of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperazin-1-yl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]=NO.[OH2:14]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:13])[C:10]2=[O:14]
Reactant: O
Reactant: O=C(C=NO)Nc1ccccc1F
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(F)cccc2C1=O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
A solution of N-(2-fluorophenyl)-2-(hydroxyimino)acetamide (35.0 g, 192 mmol) in sulfuric acid (150 mL) was heated and stirred at 70° C. for 45 minutes. The solution was allowed to cool to room temperature and poured into iced water, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crystals were collected by filtration to give the title compound (14.6 g, 46% yield).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]([CH:22]3[CH2:24][CH2:23]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO.CCOC(C)=O>[CH:22]1([N:13]2[C:14]3([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:15][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][CH:7]=3)[C:12]2=[O:25])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Reaction time: 3 h
Yield: 9.5 %

Procedure:
A solution of 76 mg (2.1 mmol) 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester in 2 ml THF/Methanol 1.1 was treated with 0.5 ml of 1N LiOH. After stirring for 3 h the reaction mixture was acidified with 1N HCL, taken up in EtOAc and washed with water to give 65.5 mg of pure 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid MS (API): 327.5 (M−H). A solution of 47 mg (1.3 mmol) 4-(1-cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid and 27 mg (0.16 mmol) of 1,1-carbonyl diimidazole in 1 ml of THF was stirred under reflux for 1 h, then 32 mg (0.4 mmol) of Ammonium acetate was added and the stirring under reflux was continued for another 2 h. The reaction mixture was taken up in EtOAc and washed with 1N HCL and water. The crude product was crystallized in Ether/Heptan to give 25 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzamide. MS (ESI): 328.4 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[C:16]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[N:18][CH:19]=3)=[CH:12][N:11](COCC[Si](C)(C)C)[C:8]2=[N:9][CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl.CS(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[C:16]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[O:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[N:18][CH:19]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cnc2c(c1)c(-c1cncc(N[C@H](C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(=O)Nc1cnc2[nH]cc(-c3cncc(N[C@H](C(=O)NCC(F)(F)F)C(C)C)c3)c2c1
Reaction time: 18 h

Procedure:
To a solution of the above residue from Step 1 in DCM (2 mL) was added TFA (2.0 mL, 26 mmol) and the resultant mixture was stirred for 2 h. The mixture was concentrated in vacuo, resuspended in MeOH (1 mL) and to this was added ethylenediamine (13 μl, 0.187 mmol) and sodium hydroxide (10 M aq) (0.065 mL, 0.653 mmol). After 18 h, the reaction was transferred to vial with an additional 1 mL of dimethylsulfoxide and this solution was purified by mass triggered reverse phase HLPC. The fractions containing product 5-2 were basified with NaHCO3, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[C:9]([NH:8][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1ccc(Br)cc1F
Product: CC(=O)Nc1cc(S(=O)(=O)O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(4-Bromo-2-fluorophenyl)acetamide (173.2 g) was suspended in conc. sulfuric acid (80 ml), and 60% fuming sulfuric acid (340 ml) was dropwise added thereto at 10 to 20° C., followed by stirring at 20° C. for 2 hours. The reaction mixture was dropwise added to ice water (500 g) at 10° to 20° C., and the precipitated crystals were collected by filtration, washed with cold water (400 ml) and dried under reduced pressure to give 175.8 g of 5-(N-acetylamino)-2-bromo-4-fluorobenzenesulfonic acid. M.P., more than 300° C.