Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:51][CH:52]([CH3:54])[CH3:53])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([N:51]([CH:52]([CH3:54])[CH3:53])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH2:49][CH3:50]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCCNC(C)C
Product: CCCCN(C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1)C(C)C

Procedure:
In a manner analogous to the method described in example 163, {1-[(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]-piperidin-4-yl}-acetic acid was coupled with n-butyl isopropyl amine (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C43H58Cl2N5O3 [(M+H)+] 762.391 1, observed 762.3908.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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(OCC)(=O)C>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[C:11]#[N:12]
Reactant: CN(C)C=O
Reactant: COc1cc(C)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C#N)c1
Temperature: 90 °C
Yield: 83 %

Procedure:
In a 100 mL round bottom flask, 1-bromo-3-methoxy-5-methyl-benzene (2.17 g, 10.79 mmol), Zn(CN)2 (1.9 g, 16.19 mmol, 1.5 eq.) and Pd(PPh3)4 (1.24 g, 1.08 mmol, 0.1 eq.) was charged with DMF (20 mL). The reaction mixture was heated at 90° C. under Ar for 7 hours. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAC/hexane) to give a white solid (1.31 g, 83%). 1H NMR (300 MHz, CDCl3): δ 7.05 (s, 1H), 6.97 (s, 2H), 3.81 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[C:5]([Cl:8])=[CH:4][S:3]1>C(O)(=O)C.[Zn]>[Cl:8][C:5]1[C:6]([OH:7])=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:3][CH:4]=1
Reactant: COC(=O)C1(Cl)SC=C(Cl)C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1scc(Cl)c1O

Procedure:
2,4-Dichloro-2-methoxycarbonylthiophene-3(2H)-one (60 mmol) in acetic acid (50 ml) was treated with metallic zinc (60 mmol) at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between water and ether. The organic phase was washed with water, dried with sodium sulphate and the solvent removed under reduced pressure to leave a solid which was crystallised from hexane m.p. 76°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[CH3:14][O:15][C:16](=[O:32])[C:17](=[CH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:25]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: COc1cccc2cc[nH]c12
Reactant: COC(=O)C(=Cc1cccnc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1cccnc1)n1ccc2cccc(OC)c21
Reaction time: 0.5 h

Procedure:
To a solution of 7-methoxyindole in DMF was added sodium hydride (0.086 g, 60% in oil) at 0° C. and the resulting mixture was stirred for 30 minutes. 2-Pyridin-3-ylmethylene-malonic acid tert-butyl ester methyl ester (0.470 g) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed twice with water and once with brine, then dried over magnesium sulfate, filtered and evaporated to dryness to afford the crude 2-[(7-methoxy-indol-1-yl)-pyridin-3-yl-methyl]-malonic acid tert-butyl ester methyl ester, which was crystallized from a hexane-ether mixture (0.207 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:13])[C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[C:14]([O-:17])([O-])=[O:15].[K+].[K+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:17])=[O:15])=[CH:7][CH:6]=1)[NH:3][C:4]2=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc2c(=O)[nH]c(Cl)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)O)cc3)cc12
Yield: 79.9 %

Procedure:
3-Chloro-5-methyl-2H-isoquinolin-1-one (50 mg, 0.26 mmol), 4-carboxybenezeneboronic acid (64 mg, 0.39 mmol), K2CO3 (73 mg, 0.52 mmol) and Pd(dppf)Cl2 (11 mg, 0.013 mmol) in DME/EtOH/H2O 4:0.5:1 (2.75 mL) were added to a microwave vial and the reaction mixture purged with N2 for 10 min. The reaction mixture was irradiated using a microwave (300 W, 120° C., 2 h). The reaction mixture was concentrated in vacuo, water added and the mixture acidified to pH2 with 0.2M HCl aq. A brown solid precipiated from the solution which was filtered and dried in vacuo, dissolved in DMF and passed through a Si-thiol cartridge, eluting with DMF (4× column volumes) and the solvent removed in vacuo. The resulting solid was triturated with MeOH, filtered and dried to give 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid as a beige solid (29 mg, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][C:14]2=[O:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][C:14]2=[O:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOC1CCC(=O)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC1CCC(=O)N1S(=O)(=O)c1ccc(N)cc1
Yield: 56.5 %

Procedure:
At ambient temperature and pressure, 4.5 g of 1-(4-nitrophenylsulphonyl)-5-ethoxypyrrolidin-2-one, dissolved in 200 cm3 of 96° ethanol is hydrogenated in the presence of palladium at 10% on charcoal. The insoluble matter is filtered off and taken up with hot chloroform, filtered, and the last filtrate is added to the alcohol solution resulting from the first filtration. After re-crystallizing the residue twice from 96° ethanol, 2.3 g of the expected product is obtained, m.p. 185°-186° C.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in a analogous manner to Example 61e. Product isolated as an off-white solid (0.013 g, 13%). MP: 170-175° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.95 (br s, 1H), 8.64 (d, 1H, J=8.3 Hz), 8.12-8.06 (m, 2H), 7.54-7.39 (m, 3H), 7.08 (t, 1H, J=7.6 Hz), 6.64 (s, 1H), 6.22-6.12 (m, 1H), 6.07-5.74 (m, 1H), 3.86 (s, 3H), 3.52 (p, 2H, J=6.8 Hz), 2.99-2.71 (m, 13H). MS: 531 (MH)+.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH2:9][Cl:10]>>[Cl:10][CH2:9][CH2:8][CH2:7][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: ClCCCBr
Product: CC(C)(C#N)CCCCl

Procedure:
reacting isobutyronitrile with 1-bromo-3-chloropropane in the presence of a first base in a non-polar solvent at a temperature of about 15°to 65°C. to afford 5-chloro-2,2-dimethylpentanenitrile;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:5]2.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:12]=[C:7]1[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[N:20])[CH:3]=2)[NH:8]1
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CN(C1CCNCC1)C(=O)N2
Temperature: 90 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
6-Bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.16 g, 0. 52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) were combined in dimethylformamide (4 mL). The reaction flask was connected to high vacuum and degassed (3×) by a freeze-thawing method, before being heated at 90° C. with stirring under nitrogen for 1 h. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture purified by preparative HPLC to afford 50 mg (38%) of the desired nitrile. 1H-NMR (CD3OD) δ 1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 (m, 1H), 4.47 (s, 2H), 6.93 (d, J=8.1, 1H), 4.10 (m, 2H). Mass spec.: 257.13 (MH)+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]([OH:27])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C(O)Cc3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2RS)-2-hydroxy-3-phenylpropanoic acid, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=483.3.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:12][CH:13]=2)=[O:7])[CH2:2]1.Cl[C:22]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[C:24]#[N:25].C(O)CCC.O>C(OCC)(=O)C.[Cl-].[Na+].O>[C:24]([C:23]1[C:22]([N:1]2[CH2:4][CH:3]([NH:5][C:6]([C:8]3[CH:13]=[N:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[N:10][CH:9]=3)=[O:7])[CH2:2]2)=[N:29][C:28]([CH3:30])=[CH:27][C:26]=1[CH3:31])#[N:25]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(C#N)c(N2CC(NC(=O)c3cnc(-c4cccc(F)c4)nc3)C2)n1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
To a vial was added N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (0.04 g, 0.13 mmol), 2-chloro-4,6-dimethylnicotinonitrile (32.5 mg, 0.19 mmol), and 0.3 mL each of n-butanol, TEA and water. The mixture was heated to 90° C. for 12 hrs and then diluted with ethyl acetate and brine. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to give a solid, which was purified by chromatography (silica, DCM to 1-5% MeOH/DCM) to give the product, N-[1-(3-cyano-4,6-dimethylpyridin-2-yl)azetidin-3-yl]-2-(3-fluorophenyl)pyrimidine-5-carboxamide (52 mg, 76%). HRMS (M+H)=403.1682 expected, 403.1750 observed.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=4)[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: COc1cc(CO)ccc1C#N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-methoxy-benzonitrile from step 2 (100 mg, 0.61 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (325 mg, 0.613 mmol) in CH2Cl2 (3 ml) was added DIEA (235 μl, 1.35 mmol) followed immediately by the addition of Tf2O (103 μl, 0.92 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (3 ml) and heated to 60° C. for 8 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([N+:32]([O-])=O)[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:36])([CH3:35])[C:19]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>[Fe].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH2:32])[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:36])([CH3:35])[C:19]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc([N+](=O)[O-])cc4c2C3=O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc(N)cc4c2C3=O)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 118.5 %

Procedure:
To the ethanol (8 ml) suspension of 4-(6,6-dimethyl-2-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P4, 103 mg, 0.204 mmol), iron powder (228 mg, 20 eq.), ammonium chloride (109 mg, 10 eq.), and distilled water (4 ml) were added and the mixture was stirred at 90° C. for 30 min. Upon the completion of the reaction, insoluble matters were filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (115 mg, 57%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2=[C:19]([Cl:22])[CH:20]=[CH:21][N:15]2[N:14]=[C:13]1[CH:23]([CH:25]1[CH2:27][CH2:26]1)O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2=[C:19]([Cl:22])[CH:20]=[CH:21][N:15]2[N:14]=[C:13]1[CH:23]([Cl:3])[CH:25]1[CH2:27][CH2:26]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c2c(Cl)ccn2nc(C(O)C2CC2)n1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1c2c(Cl)ccn2nc(C(Cl)C2CC2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
Thionyl chloride (2 M in CH2Cl2, 1.52 ml, 3.04 mmol) was added to solution of 3-benzyl-5-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.5 g, 1.52 mmol) and pyridine (0.49 mL, 6.08 mmol) in CH2Cl2 (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then quenched by pouring on to ice. The solution was treated with 1 N HCl (100 mL) and extracted with CHCl3 (3×100 mL). The combined organic extracts were washed with saturated NaHCO3 (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 4/1 hexane/EtOAc to afford the title compound (0.368 g, 70%) as a solid: 1H NMR (DMF-d7) δ 7.96 (m, 1H), 7.47–7.60 (m, 5H), 6.97 (m, 1H), 5.94 (m, 1H), 5.22 (m, 1H), 4.63 (d, 1H, J=9.99 Hz), 2.09–2.12 (m, 1H), 0.98–1.05 (m, 1H), 0.86–0.97 (m, 1H), 0.68–0.71 (m, 1H), 0.23–0.27 (m, 1H); MS (ESI+) 348 (M++H), HRMS (ESI+) calculated: 348.0670 (M++H). found: 348.0686 (M++H).
Reaction SMILES: C(=O)(OC(C)(C)C)[NH2:2].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.Cl[C:54]1[CH:55]=[N:56][CH:57]=[C:58]([F:76])[C:59]=1[N:60]1[CH2:65][CH2:64][CH:63]([S:66]([N:69]2[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]2)(=[O:68])=[O:67])[CH2:62][CH2:61]1.C(O)(C(F)(F)F)=O>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1.C(Cl)Cl>[F:76][C:58]1[C:59]([N:60]2[CH2:65][CH2:64][CH:63]([S:66]([N:69]3[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]3)(=[O:68])=[O:67])[CH2:62][CH2:61]2)=[C:54]([NH2:2])[CH:55]=[N:56][CH:57]=1
Reactant: CN1CCN(S(=O)(=O)C2CCN(c3c(F)cncc3Cl)CC2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN1CCN(S(=O)(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Tert-butyl carbamate (211.3 mg, 1.804 mmol), sodium tert-butoxide (173.4 mg, 1.804 mmol), BrettPhos Pre-catalyst (143.7 mg, 0.1804 mmol) and BrettPhos (96.83 mg, 0.1804 mmol) were degassed by vacuum/nitrogen cycles (×5). A solution of 1-[[1-(3-chloro-5-fluoro-4-pyridyl)-4-piperidyl]sulfonyl]-4-methyl-piperazine (340 mg, 0.9022 mmol) in dry toluene (9.884 mL) was added and the resulting mixture was heated to 80° C. After 5 minutes at 80° C. the reaction was cooled to RT and partitioned between ethyl acetate and water. The combined organics was dried with MgSO4 and concentrated in vacuo to a yellow solid. The yellow solid was purified by column chromatography using 1% MeOH/DCM to elute side products and then 5-10% MeOH/DCM to elute product. Relevant fractions combined and concentrated in vacuo to yield a light yellow solid. It was dissolved in DCM (10 mL) followed by the addition of TFA (1.029 g, 695.3 μL, 9.022 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to yield 5-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-amine as a light orange solid. MS (ES+) 358.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Br)cc1Sc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Sc1ccccc1)c1ccccc1
Yield: 95.6 %

Procedure:
mL 5-Bromo-3-(phenylthio)pyridin-2-amine (17 g, 60.5 mmol), benzoyl isothiocyanate (9.79 mL, 72.6 mmol), and THF (300 mL) was stirred at 40° C. overnight. Concentrated to half of the original volume and 9:1 hexanes:EtOAc (500 mL) was added. Filtered to afford the title compound (25.7 g, 95.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15].[CH:17]([N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:24]2[N:20]([CH:17]([CH3:19])[CH3:18])[N:21]=[CH:22][CH:23]=2)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Reactant: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(C)(F)F)cc1N
Temperature: 90 °C
Reaction time: 72 h
Yield: 18.4 %

Procedure:
To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.809 g, 2.37 mmol) in dioxane (10 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (1.14 g, 2.84 mmol) and Pd(PPh3)2Cl2 (170 mg, 0.237 mmol) and the resulting mixture was stirred at 90° C. for 72 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1,1-difluoro-ethyl)-5-(2-isopropyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (141 mg, 0.436 mmol, 18%) ES-MS: m/z 324 [M+H]+, rt 6.39 min.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(#N)C.CN(C)C=O>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:20](=[O:21])[O:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A solution of [3-(1H-tetrazol-5-yl)phenyl]amine (0.97 g, 0.006 mol) in acetonitrile (25 mL), dimethylformamide (3 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and was stirred at room temperature overnight The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 1M HCl, resulting in separation of a pink solid insoluble in either phase. The solid was sintered off and the organic layer was dried over magnesium sulfate, concentrated in vacuo to give additional product The two crops were combined, triturated with wet ether and dried in vacuo to yield 1.52 g of 3-(1H-tetrazol-5-yl)phenylcarbamic acid, 4-nitrophenyl ester, m.p. 186°-188° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:.2), Rf =0.65; M.S. (M+H)+ at 327, M.W. 326. This material was used without further purification.