Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH2:18][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: NCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea with excess ethylenediamine at room temperature afforded the title compound m.p. 164°-167° (from acetonitrile-ethanol)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Si:37]([C:41]#[CH:42])([CH3:40])([CH3:39])[CH3:38]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][Si:37]([C:41]#[C:42][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([CH3:40])[CH3:39]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-iodobenzamide (I29) (1.65 g, 6.66 mmol), Cu(I)I (127 mg, 0.666 mmol) and triphenylphosphine (524 mg, 2.00 mmol) in THF (100 mL) and triethylamine (4.64 mL, 33.3 mmol) was sonicated for 10 minutes under a nitrogen atmosphere. PdCl2(PPh3)2 (642 mg, 0.67 mmol) and TMS acetylene (1.88 mL, 13.3 mmol) were then added and the reaction stirred at room temperature for 3 days. The volatiles were evaporated in vacuo and the residue chromatographed on silica gel (0-50% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I30) (1.53 g); 1H NMR (400 MHz, CDCl3) δ 7.78 (t, J=1.5 Hz, 1H), 7.67 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.53-7.48 (m, 1H), 7.29 (td, J=7.8, 0.5 Hz, 1H), 0.15 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN.C(=O)(O)[O-].[K+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH2:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: NN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2-(4-nitrobenzyl)isoindoline-1,3-dione (1.6 g, 5.33 mmol) in tetrahydrofuran was added hydrazine monohydrate (4 eq). The mixture was refluxed for 6 h. After cooling down to room temperature the mixture was treated with potassium bicarbonate to pH 12˜13, extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave (4-nitrophenyl)methanamine (592 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:47][N:48]([CH3:53])[S:49]([N:27]1[CH2:26][CH2:25][N:24]([C:23](=[O:30])[C:22]([NH:21][C:18]23[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=4)=[O:9])[N:11]=[C:12]32)=[O:31])[CH2:29][CH2:28]1)(=[O:51])=[O:50]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CCN(C(=O)C(=O)NC23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a suspension of N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.025 g, 0.040 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.028 mL, 0.160 mmol) and the solution was stirred at room temperature for 5 min. Added to this was dimethylsulfamoyl chloride (4.26 μL, 0.040 mmol) and the solution was stirred at room temperature for 16 h. The reaction solution was concentrated and purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0-1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=20; Final % B=100; Gradient time=20 min; Stop time=30 min; Column=XTERRA® 19×50 mm, C18, 5 μm to give the title compound as a white solid (12.2 mg, 45% yield). LCMS (M+H) calcd for C27H35FN7O7S: 620.23; found: 620.74. 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, s), 8.45 (1 H, s), 8.39 (1 H, t, J=5.95 Hz), 7.36 (2H, dd, J=8.55, 5.49 Hz), 7.01 (2 H, t, J=8.55 Hz), 4.55 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.66 Hz), 4.02-4.09 (2 H, m), 3.52-3.61 (2 H, m), 3.26-3.36 (2 H, m), 3.18-3.26 (2 H, m), 2.84 (6 H, s), 2.58 (2 H, ddd, J=14.19, 9.16, 5.65 Hz), 2.50 (1H, brs), 1.86-2.11 (4 H, m), 1.66-1.80 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:26]([C:29]([NH:31]C(C)(C3C=CC=CC=3)C)=[O:30])=[CH:27][N:28]=2)[C:21]([O:23]CC)=[O:22])[CH2:14][C@H:13]1[O:41][CH3:42])=[O:10].Cl>CO.O>[NH2:31][C:29]([C:26]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@H:13]([O:41][CH3:42])[CH2:14]2)=[N:28][CH:27]=1)=[O:30]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)NC(C)(C)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CO[C@@H]1CN(c2cc(C(=O)O)c(C(N)=O)cn2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 120 °C
Yield: 10 %

Procedure:
A mixture of 85 mg (0.17 mmol) of Cis(±)-ethyl 5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 198) and 86 mg (0.50 mmol) Ba(OH)2 in 3 ml MeOH and 2 ml water was heated at 120° C. for 1 h. The mixture was acidified to about pH=4 with 1N HCl and extracted 4 times with EtOAc. The EtOAc was concentrated and the residue was purified by reverse phase HPLC (20-40% CH3CN gradient in water with 0.1% TFA) to afford 8 mg of product as a white solid. MS (ES) MH+: 470 for C19H21Cl2N5O5; NMR: 1.5-1.8, (m, 3H), 2.2 (s, 3H), 3.0-3.2 (m, 2H), 3.3 (s, 3H), 3.5 (m, 2H), 4.2-4.5 (m, 2H), 4.9 (d, 1H), 6.9 (s, 1H), 7.1-7.3 (m, 2H), 7.8 (s, 1H), 8.4 (s, 1H), 12.1 (s, 1H), 13.1 (s, 1H).
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S([C:13]2[C:22]3[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[N:15][CH:14]=2)(=O)=O)=CC=1>CN(C=O)C>[C:1]([C:13]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1)#[N:2]
Reactant: [C-]#N
Reactant: CCc1cccc2c(S(=O)(=O)c3ccc(C)cc3)cnnc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc2c(C#N)cnnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of potassium cyanide was added to a stirred solution of 4.4 g of 53F in 60 ml of dry DMF at room temperature, under nitrogen. The mixture was stirred overnight at room temperature, under nitrogen, then 200 mg potassium cyanide was added and the mixture was stirred for 5 hours at room temperature. The mixture was quenched in water and filtered. The solid was dissolved in ethyl acetate, the solution was washed with water, dried (MgSO4), filtered and stripped of solvent, to give 4-cyano-8-ethylcinnoline (53G), as a yellow solid, m.p.: 102°-104° C., with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCCOCc2ccccc2)cc1N

Procedure:
1.6 G. of 2-amino-4-(2-benzyloxyethoxy)-1-nitrobenzene is treated in 100 ml. of methanol and 50 ml. of water with 10 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for 15 minutes. The reaction mixture is concentrated under vacuum and extracted with chloroform. Evaporation of the extract affords 1,2-diamino-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](OCC)=[O:6])(=O)[CH3:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C>[NH2:21][C:19]1[N:20]=[C:5]([OH:6])[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:1]([CH3:2])[N:18]=1
Reactant: N=C(N)N
Reactant: CCCCC(C(C)=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CCO
Product: CCCCc1c(C)nc(N)nc1O
Yield: 47.6 %

Procedure:
A mixture of ethyl 2-acetylhexanoate (5.59 g, 30 mmol), guanidine carbonate (6.49 g, 30 mmol) and ethanol (20 ml) was refluxed for 11 hours and then ice-cooled. The precipitated crystals were filtered, washed with ethanol and dried in vacuo to give 2-amino-5-butyl-6-methylpyrimidine-4-ol (2.59 g, 47%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(=O)C(C)(C)C)O2)c1

Procedure:
1-(3-Azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-2(1H)-pyrimidinone (0.4 g, 1.59 mMol) was dissolved in dry pyridine (10 mL) at 0° C. under a nitrogen atmosphere. Pivaloyl chloride (0.588 mL; 4.78 mMol) was added with stirring and allowed to react for 72 hours. The reaction was quenched with ice then evaporated to dryness. The residue was chromatographed on silica gel eluted with 20:1 CHCl3 /MeOH (v/v) and the appropriate fractions combined and evaporated to give the title compound: mp =121°-123° C.; UV (nm): at pH 1λmax =327 (ε=5900), λmin =269 (ε=820); at pH 13λmax =322 (ε=17200), λmin =251 (ε=850); 1H NMR: (DMSO-d6) δ8.48(d, J=3.12 Hz, 1H, H4), 7.88(d, J=3.27 Hz, 1H, H6), 6.02(t, J=6.25 Hz, 1H, H1 '), 4.48-4.39(m, 1H, H3 '), 4.31-4.28(m, 2H, H5 '), 4.20-4.14(m, 1H, H4 '), 2.62-2.50(m, 1H, H2 '), 2.41-2.27(m, 1H, H2 '), 2.04(s, 3H, 5-CH3), 1.12(s, 9H, -C(CH3)3).
Reaction SMILES: [CH3:1][C:2]1[C@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][C:13]#[CH:14].O>C(Cl)(Cl)Cl>[OH:7][C@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][C:13]#[CH:14])=[C:2]1[CH3:1]
Reactant: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#CCC1=C(C)[C@@H](O)CC1=O
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 1.95 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one and 30 ml of water was stirred at a temperature of 85°-90° C. for 4 hours. Thereafter, with the same operations as in Example 3, 1.35 g of (S)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one (chemical purity: 90.2%, [α]D24 : +13.1° (C=1.07, in chloroform), (R)-isomer/(S)-isomer=16.2/83.8) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[N:12]1[C:17]2[NH:18][C:19]3[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=3[N:21]([C:23]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])=[O:24])[CH2:22][C:16]=2[CH:15]=[CH:14][CH:13]=1>CCCCCC>[F:35][C:32]([F:33])([F:34])[C:26]1[CH:27]=[C:28]([N:7]2[CH:8]=[CH:9][C:5]([C:4]([F:11])([F:10])[F:3])=[N:6]2)[CH:29]=[CH:30][C:25]=1[C:23]([N:21]1[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]=2[NH:18][C:17]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:22]1)=[O:24]
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Yield: 58.4 %

Procedure:
Sodium hydride (60% suspension in oil, 0.17 g, 4.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). 3-trifluoromethyl pyrazole (0.34 g, 2.5 mmol) was added in one portion. After the gas evolution subsided stirring was continued at room temperature. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-methanone of Example 4, Step B (0.75 g, 1.94 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) overnight. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was crystallized from ethanol to yield the title compound (0.57 g) as an off-white solid, m.p. 127-129° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].Cl.[NH2:14][OH:15].[OH-].[Na+]>O>[F:1][C:2]([F:12])([F:11])[C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[O:15][N:14]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(c1cc(N)on1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) and hydroxylamine hydrochloride (0.407 g, 5.86 mmol) in water (30 mL) was added NaOH (0.447 g, 11.16 mmol). Then the mixture was stirred at 100° C. for 3 h. After cooling to rt, the mixture was extracted with DCM (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a light yellow solid of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (700 mg, 3.39 mmol, 61% yield): 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 1H), 4.41 (s, 2H), 1.49 (s, 6H); ES-LCMS m/z 195 (M+H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.0 g (6.51 mmol) of 3-[3-(imidazo-[1,2-a]pyridin-5-ylthio)propyl]thiazolidine-2,4-dione and 0.59 ml (6.51 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.65 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/4) to yield 1.57 g (66.7%, light orange oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH4+:10].[OH-]>>[Br:8][C:6]1[N:7]=[C:2]([NH2:10])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Clc1ncc(Br)nc1Br
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nc(Br)cnc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Into a 250 mL sealed tube was placed compound 90d (50.0 g, 184 mmol) and NH4OH (150 mL). The resulting mixture was stirred overnight at 100° C. Upon cooling, a solid was collected by filtration and dried in an oven under reduced pressure to obtain the compound 90e as a grey solid (28.0 g, 66% yield), which was used in next step without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:32]N>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:32][N:2]=[CH:3][CH:4]=2)=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 40 above, using compound B 6-(3-dimethylaminoacryloyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:20])[NH:5]1)[CH:2]=C.CC([OH:31])(C)C>C1COCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@:4]([CH2:1][CH2:2][OH:31])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:5][C:6]2=[O:20])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@@](CCO)(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 1517.5 %

Procedure:
To a stirred solution of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (51 mg, 0.12 mmol) in THF (2 mL) and water (2 mL) were added NaIO4 (132 mg, 0.62 mmol) and 2.5% OSO4 in t-BuOH (0.032 mL, 0.003 mmol). The mixture was stirred at rt for 5 h and concentrated under reduced pressure. The residue was partitioned between EtOAc (90 mL) and brine (20 mL). The organic layer was concentrated and the residue was dissolved in MeOH (20 mL). The solution was cooled in an ice bath and NaBH4 (50 mg) was added. The mixture was stirred overnight and concentrated. The residue was taken up in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (43 mg) which was purified by prep HPLC to afford (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl-1,3-diazepan-2-one (19 mg, 37%) as an oil. LC-MS Method 2 tR=8.7 min, m/z=419, 417; 1H NMR (CDCl3) δ 1.0-1.2 (2H), 1.23 (d, 3H), 1.77 (m, 1H), 2.01 (m, 1H), 2.24 (m, 2H), 2.66 (m, 1H), 2.89 (m, 1H), 3.45 (m, 1H), 3.72 (m, 1H), 4.10 (br s, 1H), 5.50 (q, 1H), 6.79 (s, 1H), 7.24 (3H), 7.37 (2H), 7.43 (4H)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:10])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 75 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 75%). MS (m/e): 447.3 (M+H+, 100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](SC)[S:14][CH3:15])[C:11]#[N:12].O.[NH2:19][NH2:20].O>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:12])=[N:19][NH:20][C:13]=1[S:14][CH3:15]
Reactant: NN
Reactant: CSC(SC)=C(C#N)c1nc2ccccc2s1
Solvent: CCO
Solvent: O
Product: CSc1[nH]nc(N)c1-c1nc2ccccc2s1
Yield: 44 %

Procedure:
To a suspension of 2-benzothiazol-2-yl-3,3-bismethylsulfanylacrylonitrile (50 mg, 0.18 mmol) in ethanol (2 mL) was added hydrazine hydrate (15 μL). The mixture was heated to reflux for 2 hours. The reaction mixture was then cooled and water was added. The resulting precipitate was isolated by filtration to yield 21 mg (44%) of the title compound as a yellow solid. MS (m/z, ES+): 263 (M+1, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:23]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:24])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
To a suspension of phenylalanine methyl ester hydrochloride (2.15 g, 10.0 mmols) in methylene chloride (40 mL) at -30° C. was added N-methylmorpholine (2.2 mL, 20 mmols) followed by p-nitrophenyl chloroformate (2.01 g, 10 mmols). The resulting mixture was stirred at -30° C. for 15 minutes, then for 15 minutes at 25° C., after which it was washed sequentially with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried, and concentrated. The residue (2.96 g) was crystallized from acetonitrile to give the title A compound (1.22 g), m.p. 130°-131° C., [α]D +88° (c=1.5, CHCl3). The mother liquor was chromatographed on silica gel (90 g), eluting with benzene:ethyl acetate (9:1) to give an additional 760 mg of the title A compound (total yield 1.98 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1.CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:21]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-3-nitrobenzaldehyde (5.00 g, 29.9 mmol) in tetrahydrofuran/DMF (300 mL/120 mL) was added NaH (60%, 1.32 g, 32.9 mmol), followed by ethyl bromoacetate (5.49 g, 3.65 mL, 32.9 mmol). The mixture was heated at reflux for 20 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), acidified to pH 2 with 1N HCl, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL), the organic extracts were combined and washed with saturated NaHCO3 (2×50 mL), brine (1×50 mL), dried over MgSO4, and concentrated to an amber oil. Purification of the residue by silica gel flash chromatography (25% ethyl acetate/hexanes) afforded the title compound. 1H NMR (DMSO-d6) δ 1.91 (t, J=7.08 Hz, 3H), 4.16 (q, J=7.08 Hz, 2H), 5.15 (s, 2H), 7.50 (d, J=8.79 Hz, 1H), 8.12–8.14 (m, 1H), 8.42 (d, J=1.95 Hz, 1H), 9.93 (s, 1H) ppm. MS: M+−1=252.1 Da.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2>>[CH3:27][C:21]1[N:22]=[C:23]2[C:18]([C:17]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Oc2ccccc2)c(N)c1
Product: Cc1ccc(Oc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 41b (65 mg, 0.36 mmol) was reacted with the product from Example 1d following the procedure from Example 1g giving the tile compound that was triturated with ether giving the product as a hydrochloride salt (12 mg, 8.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.73 Hz, 3H) 1.82 (q, J=7.72 Hz, 2H) 2.97 (dd, J=7.73 Hz, 2H) 6.68 (d, J=6.99 Hz, 1H) 6.99 (d, J=7.72 Hz, 2H) 7.12 (dd, J=8.82 Hz, 2H) 7.30 (dd, J=8.09 Hz, 2H) 7.66 (dd, J=8.82 Hz, J=2.58 Hz, 1H) 7.71 (d, J=2.2 Hz, 1H) 7.77 (d, J=8.82 Hz, 1H) 8.52 (d, J=6.98 Hz, 1H) 9.07 (d, J=8.82 Hz, 1H) 11.26 (br s, 1H) 14.45 (brs, 1H); MS (ESI+) m/z 390 (M−Cl)+; (ESI−) m/z 388 (M−HCl)−.