Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52](Cl)=[O:53])[C:33]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)([CH3:44])[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]([C:52]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:9][CH2:10]3)=[O:53])[C@@:33]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)([CH3:44])[C@@:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)([CH3:36])[N:35]=2)=[C:27]([O:55][CH2:56][CH3:57])[CH:26]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-Methanesulfonyl-propyl)-piperazine (30 mg, 0.11 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) was suspended in 5 mL of methylene chloride and cooled to 0° C. Triethylamine was added followed by drop wise addition of rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride in 2 mL of methylene chloride. The mixture was stirred at room temperature for 30 min and then taken up in methylene chloride and washed successively with 10% sodium hydrogen carbonate and water. The methylene chloride phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with methylene chloride/methanol (95:5) gave rac-[(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone as a white solid (16 mg). HR-MS (ES, m/z) calculated for C37H48N5O4SCl2 [(M+H)+] 728.2799, observed 728.2793.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]([F:10])([F:9])[CH2:5][N:6]=[C:7]=[S:8]>CCO>[F:3][C:4]([F:10])([F:9])[CH2:5][NH:6][C:7]([NH:1][NH2:2])=[S:8]
Reactant: NN
Reactant: FC(F)(F)CN=C=S
Solvent: CCO
Product: NNC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.634 mL, 20.20 mmol) (Sigma-Aldrich) was added to a stirring solution of 1,1,1-trifluoro-2-isothiocyanatoethane (2.85 g, 20.20 mmol) in EtOH (80 mL). The reaction was stirred at RT for 2 h. The solvent was removed in vacuo to give N-(2,2,2-trifluoroethyl)hydrazinecarbothioamide, and the material was used without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([C:14]([C:20]#[N:21])=[C:15](SC)[S:16][CH3:17])#[N:13]>>[C:12]([C:14]([C:20]#[N:21])=[C:15]([S:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Cc1nc[nH]c1CSCCN
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N

Procedure:
Reaction of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole with 1,1-dicyano-2,2-bis methylthioethylene by the procedure of Example 8(i) yields 1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.C(O[CH:20](OC(C)(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C.C(OCC)(=O)C>CN(C=O)C>[CH3:20][N:21]([CH:23]=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:22]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2c(ccc3ncccc23)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-H-pyrrolo[3,2-f]quinoline-2-one (13 mmol) and dimethylformamide di-t-butyl acetal (15 mmol) in DMF was stirred at room temperature for 3 h. Ethyl acetate (25 mL) was added and the resulting solid was collected by filtration and allowed to air dry. The desired compound was obtained (70%) and used directly in the next step.
Reaction SMILES: [CH3:1][NH2:2].CS([C:7]1[N:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:9]([CH3:17])[N:8]=1)(=O)=O>C(Cl)Cl>[CH3:1][NH:2][C:7]1[N:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:9]([CH3:17])[N:8]=1
Reactant: Cc1cc(OC(F)F)nc(S(C)(=O)=O)n1
Reactant: CN
Solvent: ClCCl
Product: CNc1nc(C)cc(OC(F)F)n1
Yield: 74 %

Procedure:
30 ml of a 40% aqueous methylamine solution are added, at a temperature of between 20° and 25° C., to 2.2 g (0.009 mol) of 2-methylsulfonyl-4-difluoromethoxy-6-methylpyrimidine. The mixture warms up to a temperature of 60° C. The reaction mixture is subsequently stirred for half an hour at the same temperature; it is then cooled and 50 ml of methylene chloride are added. The organic phase is separated, dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from a methylene chloride/petroleum ether mixture yields 1.4 g (74% of theory) of 2-methylamino-4-difluoromethoxy-6 -methylpyrimidine, m.p. 129.5°-131° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9]1
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Temperature: 120 °C
Yield: 98.3 %

Procedure:
A mixture of 2-fluoropyridine (1.0 g, 10.3 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (1.80 g, 9.66 mmol) was heated at 120° C. for 5 h. After cooling to RT, the solid formed was treated with ether, filtered, and washed with ether. The solid was collected and dried to give the desired product (2.50 g, 98.2%). LCMS: (M+H)=264.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 2.58 g, 14.2 mmol) and triethylamine (1.43 g, 14.2 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.63 g, 14.2 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 3.15 g (85%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 261 (MH+); [α]D+53.8 (c, 1.1, MeOH).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Yield: 86.6 %

Procedure:
Pyrrolidine (0.065 mL, 0.8 mmol) was added to a solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 0.2 g, 0.65 mmol) and triethylamine (0.18 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give 0.2 g of the title compound as a solid, mp>250° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)O1.Br[C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.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>[C:51]([O:50][C:48]([NH:47][C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([C:24]([F:25])([F:26])[F:27])[CH:10]=2)=[CH:35][N:34]=1)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:49])([CH3:53])([CH3:54])[CH3:52]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)(C(=O)OCC)c1ccc(Br)cn1
Reactant: CCCCCCCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC)nc2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
The suspension of 4,4,5,5-tetramethyl-2-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane 3a (136 mg, 0.34 mmol, 1.5 equiv), diethyl 2-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)malonate (98 mg, 0.23 mmol, 1.0 equiv), Pd(PPh3)4 (26.3 mg, 0.023 mmol, 0.1 equiv), and Na2CO3 (120 mg, 1.14 mmol, 4.0 equiv) in ethanol-H2O was heated at 80° C. for 1 hour. The reaction mixture was filtered and the filtrate was purified by silica gel column to afford the title compound in 77% (110 mg) yield. MS (ESI, M+H+)=625.1; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.88 (s, 1H), 7.86 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.75 (d, J=2.5 Hz), 7.66 (d, 1H, J=8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 4.30 (m, 4H), 4.09 (t, 2H, J=6.0 Hz), 1.84 (m, 2H), 1.46 (m, 11H), 1.28 (m, 14H), 0.90 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:39]=[CH:38][C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH2:26][CH2:25]4)[C:15](=[O:23])[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:39]=[CH:38][C:12]3[N:13]=[C:14]([N:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)[C:15](=[O:23])[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCOCCn1c(=O)c(N2CCN(CC(=O)OC(C)(C)C)CC2)nc2cnc(-c3ccc(OC)nc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOCCn1c(=O)c(N2CCN(CC(=O)O)CC2)nc2cnc(-c3ccc(OC)nc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of tert-butyl {4-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihydropyrido[3,4-b]pyrazin-3-yl]piperazin1-yl}acetate (174 mg, 0.32 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, concentrated and recrystallized from ethyl acetate and hexane and filtered. The {4-[7-(6-methoxypyridin-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dihydropyrido[3,4-b]pyrazin-3-yl]piperazin1-yl}acetic acid was obtained as a white solid. (81 mg, 52% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: CNCCc1ccc(C(=O)OC)cc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2b produced 3g. MS found M+H=453. The oxalate salt of 3g was recrystallized from ethyl acetate; mp 130-131° C.
Reaction SMILES: [C:1]([C:3]1[CH:40]=[CH:39][C:6]([O:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:27]=3)=[CH:17][CH:16]=2)[C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:40]=[CH:39][C:6]([O:7][CH:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:27]=3)=[CH:19][CH:20]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 79.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-cyanophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (244 mg), which is the product of Example 128, was reacted with aqueous sodium hydroxide solution (1N, 0.92 ml) and the reaction mixture was treated to give the title compound (184 mg) as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CO>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15](=[N:8][OH:9])[NH2:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: NC(=NO)c1ccc(Br)cc1
Yield: 109.4 %

Procedure:
To a stirred solution of ice cooled methanol (115 ml), under argon, was added potassium tert-butoxide (10.12 g. 0.09 mol), portionwise. After stirring for 5 minutes hydroxylamine hydrochloride (6.71 g, 0.097 mol) was added in one portion. After stirring for 1 hour at room temperature a slurry of 4-bromobenzonitrile, (10.88 g, 0.06 mol) in methanol (150 ml) was added. The mixture was then heated at reflux for 4 hours, cooled and filtered. The filtrate was evaporated in vacuo to give the title compound as a colourless solid (14.12 g, quant.)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=O)[CH:32]=[N:33][CH:34]=1.C([BH3-])#N.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:35][C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Reactant: O=Cc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2sc(NCc3cncc(F)c3)nc2Cl)c2cc(Cl)cnc21
Yield: 49.7 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 50.0 mg, 0.11 mmol, prepared as described in Example 66, Scheme 183) in ethanol (1.60 mL) and acetic acid (0.08 mL) were added 5-fluoro-pyridine-3-carbaldehyde (594, 43 mg, 0.34 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction was irradiated with microwave on 300 watts, 100° C. for 7 minutes. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (595, 0.030 g, 48%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][O:17]1>>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:16](=[O:15])[O:17][CH2:18][CH2:19][C:20]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=3)[NH:16][N: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.[CH2:25]([NH2:28])[CH2:26][NH2:27].[BH4-].[Na+].Cl>CO>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:27][CH2:26][CH2:25][NH2:28])[CH:21]=3)[NH:16][N: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
Reactant: NCCN
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCNCc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reaction time: 24 h

Procedure:
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.3 mmol) was stirred for 24 hrs with the excess of ethylene diamine (1 mmol) in methanol. Sodium borohydride (0.6 mmol) was added and stirring continued for another 24 hrs. After completion, the volatiles were removed in vacuo, crude material diluted with cold water, acidified to pH 3.4, filtered off, washed on a filter with cold water and dried to afford the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCl and the evacuation of the volatiles in vacuo to afford the title compound, mp>200° C.; MS (ES+) 381[M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][C@H:19]([CH3:23])[C:20]([NH2:22])=[O:21].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:18]([C@H:19]([CH3:23])[C:20]([NH2:22])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 52 °C
Reaction time: 3 h

Procedure:
To a solution of 5-nitro-isochromen-1-one (2 g, 0.01 mol) in methanol (40 mL, 1 mol) was added (R)-2-aminopropanamide hydrochloride (2.0 g, 0.016 mol) and triethylamine (2.6 mL, 0.019 mol) and stirred at 52° C. for 3 hr. The product (yellow solid) precipitated out and was filtered and carried on to the next reaction. MS m/z=262.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][OH:16].[OH-].[K+]>CN(C)C=O>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][O:16][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC(C)CCO
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CCOCc1cccc([N+](=O)[O-])c1

Procedure:
158.1 g (0.92 mol) of 3-nitrobenzyl chloride was dissolved in a mixture of 500 ml (4.59 mol, 5 equivalents) of 3-methyl-1-butanol and 140 ml of dimethylformamide. To the resultant mixture 78 g (1.39 mol, 1.5 equivalents) of KOH pellets were added while the mixture was being cooled in a water bath and stirred strongly. The reaction temperature was elevated to 43° C. and thereafter gradually restored to room temperature. After the mixture was stirred for 7 hours at room temperature, the reaction was completed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.[I:26][C:27]1[CH:42]=[CH:41][C:30]([CH2:31][NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(I)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (1.38 g, 3.92 mmol), tert-butyl 2-((4-iodobenzyl)amino)acetate INT-35 (1.36 g, 3.92 mmol) and TEA (0.82 ml, 5.88 mmol) in DMF (8 mL) was added HATU (1.56 g, 4.11 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EA (150 mL) and washed successively with NaHCO3 (100 mL) and brine (100 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 2.05 g (75%) of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36. LCMS-ESI (m/z) calculated for C30H30F3IN2O5: 682; found 627 [M−tBu+H]+, tR=2.90 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 7.76-7.68 (m, 2H), 7.62 (dd, J=7.0, 1.8 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.27-7.13 (m, 3H), 7.12-6.97 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 3.92 (m, 2H), 3.85 (s,2H), 3.83 (s, 3H), 1.41 (s, 4.5H), 1.31 (s, 4.5H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([F:15])=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[CH2:18]([N:9]1[C:8]2[CH:14]=[C:4]([NH2:3])[C:5]([F:15])=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH:17]=[CH2:16]
Reactant: Nc1cc2c(cc1F)OCC(=O)N2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)COc2cc(F)c(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
While kept under N2, 2.41 g (60.4 mmol) of sodium hydride (60% dispersion in oil) was washed with 10 ml hexanes and then suspended in 20 ml anhydrous dimethylformamide. A solution of 10.0 g (54.9 mmol) of 6-amino-7-fluoro-2H-1,4-benzoxazin-3(4H)-one in 100 ml of dimethyl formamide was added to the sodium hydride slurry slowly by syringe with ice cooling and the reaction mixture was stirred at room temperature for 0.5 hr. Then there was added 7.91 g (65.9 mmol) of allyl bromide by syringe with ice bath cooling. The reaction mixture was allowed to warm to room temperature, and then poured into 100 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml) and the organic layers were combined and washed with water (3×50 ml), dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield 11.0 g (90% yield) of 4-allyl-6-amino- 7-fluoro-2H-1,4-benzoxazin-3(4H)-one as a brown solid.