Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].Cl>C(O)(=O)C.O>[C:14]([C:4]1[C:5]([CH3:13])=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[S:10][CH2:9][CH2:8][C:7]2=[O:12])([OH:16])=[O:15]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)O)cc(Cl)c2c1C(=O)CCS2
Temperature: 25 °C
Yield: 89 %

Procedure:
2.0 Grams (7.0 mmol) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one was dissolved in 10 ml of acetic acid, and 10 ml of a 4N hydrochloric acid aqueous solution was added. The mixture was refluxed under heat for 5 hours. After allowed to cool to room temperature, the reaction mixture was diluted with about 100 ml of water, and a precipitated solid was extracted with ethyl acetate. A carboxylic acid component was extracted from an organic layer with a saturated sodium hydrogencarbonate aqueous solution, and an aqueous layer was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated solid was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 1.6 g (yield 90%) of 6-carboxy-8-chloro-5-methylthiochroman-4-one in the form of a white solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:10])[C:3](F)([F:8])[C:4]([F:7])([F:6])[F:5].C(Cl)(C(Cl)(F)F)C(F)(F)F.C(Cl)(F)C(F)(F)C(Cl)(F)F>>[Cl:1][C:2]([Cl:10])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)(F)C(F)(F)C(Cl)Cl
Agent: FC(Cl)C(F)(F)C(F)(F)Cl
Agent: FC(F)(F)C(Cl)C(F)(F)Cl
Product: FC(=C(Cl)Cl)C(F)(F)F

Procedure:
As a mixture of dichloropentafluoropropane (HCFC-225) isomers, ASAHIKLIN AK-225 (tradename, manufactured by Asahi Glass Company, Limited, mixture of HCFC-225 isomers comprising HCFC-225ca (1,1-dichloro-2,2,3,3,3-pentafluoropropane, CHCl2CF2CF3: 48 mol %) and HCFC-225cb (1,3-dichloro-1,2,2,3,3-pentafluoropropane (CHClFCF2CClF2: 52 mol %)) was used as the reaction raw material, and 1,1-dichloro-2,3,3,3-tetrafluoropropene (CF3CF═CCl2, CFO-1214ya) was produced by the following process.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[OH:22][C:17]1([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CCCC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of tert-butyl acetate (5.0 g, 42.8 mmol,) in THF (20 mL) was added lithium diisopropylamide (21.4 mL, 42.8 mmol) at −60° C. After stirred at −60° C. for 30 min, cyclopentanone (3.0 g, 35.7 mmol) was added at −60° C. The reaction was stirred 1 h; then it was quenched with aqueous ammonium chloride (5 mL) at −60° C. and the mixture was warmed to room temperature. The reaction was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give tert-butyl 2-(1-hydroxycyclopentyl)acetate (5.0 g, 70.1% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][O:82][CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][O:82][CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:32])[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3C(F)(F)F)ncc21
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.024 g (0.237 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0439 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-3-trifluoromethyl-benzamide (I-207) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:30][C:28](=[O:29])[CH2:27][C:26]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Yield: 61.5 %

Procedure:
Following the general procedure of Example 8, 196 mg (0.58 mmole) of 5,5-bis(4-fluorophenyl)-4-(1 H-tetrazol-1-yl)-2,4-pentadienal was condensed with two equivalents (1.2 mmoles) of the dianion of ethyl acetoacetate. The product thereby produced was purified by silica gel chromatography using ethyl acetate-hexanes as eluent to yield 173.8 mg (61.5%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CC(N(C)C)=O>[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH:33][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccc4[nH]ccc4c3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc(-c3ccc4[nH]ccc4c3)c3ccccc3n2)cc1
Temperature: 50 °C
Yield: 4.4 %

Procedure:
To a round bottomed flask containing 4-(4-(1H-indol-5-yl)quinazolin-2-ylamino)-benzoic acid (428 mg, 1.13 mmol) was added 2,6-dimethylaniline (137 mg, 1.13 mmol), HATU (428 mg, 1.13), Hunig's base (400 μL, 2.3 mmol), and dimethylacetamide (4 mL). The stirred mixture was heated to at 50° C. for 14 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 5% aqueous lithium chloride and saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude material was purified by preparative reverse phase HPLC to afford N-(2,6-dimethylphenyl)-4-{[4-(1H-indol-5-yl)quinazolin-2-yl]amino}benzamide as a yellow solid (24 mg, 5%). 1H NMR (400 MHz, DMSO-d6): δ 11.45 (s, 1H), 10.23 (s, 1H), 9.60 (s, 1H), 8.19 (d, 2H), 8.02 (m, 4H), 7.83 (m, 2H), 7.62 (m, 2H), 7.51 (m, 1H), 7.41 (m, 1H), 7.13 (s, 3H), 6.63 (m, 1H), 2.20 (s, 6H). MS (EI) C31H25N5O: 484.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1
Reaction time: 1.5 h

Procedure:
To a cooled (0°) mixture of 4.07 g. (0.018 mol.) of 2-p-methoxyphenylbenzofuran and 4.17 g. (0.027 mol.) of p-toluic acid chloride in 100 ml. of methylene chloride was added dropwise 11.25 g. (0.043 mol.) of stannic chloride. The reaction mixture was stirred for 1.5 hours at 0°, then for 0.5 hour at 25 °. The mixture was poured into water and stirred vigorously, the layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated to give 2-p-methoxyphenyl-3-p-methylbenzoylbenzofuran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C#N)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reaction time: 5 h
Yield: 88.5 %

Procedure:
8.56 g (36.7 mmol) of 2-(3-cyano-phenoxy)-2-methyl-propionic acid ethyl ester was dissolved in 65 ml ethanol; then, 6.5 ml acetic acid was added, followed by 0.9 g Pd—C (10%) and the reaction mixture was hydrogenated under 1 atm of H2-pressure during 5 hours. Then, it was filtered (Celite), the filter cake was washed twice with ethanol and the solvents were evaporated. The residue was partitioned between crashed ice/1N NaOH/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 7.71 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:15][CH:16]=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH:22]=[O:23])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C@H:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:31]([CH3:38])([CH3:37])[C:32](=[O:36])[CH:33](Br)[CH3:34]>C1COCC1.[Cl-].[Na+].O>[CH3:26][O:27][C:28](=[O:47])[CH2:29][CH:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[C:31]([CH3:37])([CH3:38])[C:32](=[O:36])[CH:33]([CH3:34])[CH:22]([OH:23])[CH:21]([CH3:24])[CH2:20][CH2:19][CH2:18][C:17]([CH3:25])=[CH:16][CH2:15][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1
Reactant: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br
Reactant: CC(=O)OC(CC=C(C)CCCC(C)C=O)C(C)=Cc1csc(C)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 240 mg (1.95 mmol) CrCl2 and 125 mg (0.93 mmol) in 10.0 mL absolute THF was added 322 mg (0.886 mmol) 3-acetoxy-2,6,10-trimethyl-1-(2-methyl-thiazol-4-yl)-11-oxo-undeca-1,5-diene (8 b) in 1.0 mL absolute THF and 384 mg (0.971 mmol) (3S)-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid methyl ester (235) at ambient temperature. After stirring for 2 h 15 min at ambient temperature, 12 mL brine were added and stirring was continued for five minutes. The waterphase was extracted five times with 15 mL of a pentane-diethylether-mixture (1:5) and the combined organic layers were washed twice with 20 mL demi water and twice with 20 mL brine. After drying over Na2SO4, filtration and concentrating in vacuo, the obtained oil was purified by flash chromatography (column dimensions: 2.0×20.0 cm, diethylether/petroleum ether=5:4).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]2[C:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][C:14]3[CH2:15][CH:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:13]=3[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>>[NH:51]1[C:1]([C:3]2[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]3[C:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][C:14]4[CH2:15][CH:16]([CH2:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[O:17][C:13]=4[CH:12]=3)=[CH:5][CH:4]=2)=[N:2][N:53]=[N:52]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(OCCCc2cc3c(cc2OCc2ccccc2)CC(CCc2ccccc2)O3)cc1
Product: c1ccc(CCC2Cc3cc(OCc4ccccc4)c(CCCOc4ccc(-c5nnn[nH]5)cc4)cc3O2)cc1

Procedure:
A mixture of 6-[3-(4-cyanophenoxy)propyl]-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran E22 (1 gm, 2.0 mmoles) and tri-n-butyl tin azide (2.2 gm; 6.6 mmoles) was heated in an oil bath at 125° C. for 90 minutes. The total mixture was chromatographed on silica gel using 1:1 ethyl acetate in hexane and containing 10% acetic acid to yield 1.2 gm of 6-{3-[4-(1H-tetrazol-5-yl)phenoxy]propyl}-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E23.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:11][C:12](=[O:26])[CH2:13][C:14]1[C:15]([NH2:25])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8]CC.[CH3:27][C:28](=O)[CH2:29][C:30](=O)[CH3:31].Cl>C(O)C>[CH2:7]([O:11][C:12](=[O:26])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:27])=[N:25][C:15]=12)[CH3:8]
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(-c2ccccc2)nn2c(C)cc(C)nc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 20.0 g (0.055 mole) of 3-amino-5-phenyl-1H-pyrazole-4-acetic acid butyl ester ethanedioate and 5.51 g (0.055 mole) of pentane-2,4-dione in 150 ml of 200 ethanol was treated with 10 ml of concentrated hydrochloric acid and stirred at room temperature for 17 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:28]=4[CH:27]=[N:26][NH:25]5)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1cccc2[nH]ncc12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccc4[nH]ncc34)c2n1C
Temperature: 140 °C
Yield: 39.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 min at 140° C. by microwave irradiation. 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 30 min at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 426 as a white solid (0.044 g, 40%). LCMS (Method K): RT 2.82, 2.99 min [M+H]+ 428.1. 1H NMR (DMSO-d6, 400 MHz): δ 13.30 (1H, s), 8.23-7.98 (1H, m), 7.77-7.60 (4H, m), 7.51-7.48 (1H, m), 7.36-7.24 (2H, m), 7.23-7.08 (2H, m), 5.59-5.54 (1H, m), 3.00 (3H, d, J=8.05 Hz), 1.57 (3H, dd, J=6.69, 1.65 Hz). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1I.Cl>CN1CCCC1=O>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[S:1][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[OH:13])[C:18]([OH:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CO)c(S)c1
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(O)c(Sc2cc([N+](=O)[O-])ccc2CO)c1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of 2-mercapto-4-nitrobenzyl alcohol (3.49 g, 18.86 mmoles), 4-hydroxy-3-iodo-benzoic acid (4.67 g, 17.69 mmoles), red cuprous oxide (1.35 g, 9.44 mmoles) and 1-methyl-2-pyrrolidinone (40 ml) was heated under a N2 atmosphere. The mixture became a thick slurry at about 90° but at 130° had become a dark red solution. After 1/2 hour at 140° TLC showed that the reaction was finished. The mixture was poured onto 2N HCl (200 ml) and after stirring for a few minutes it was extracted 4× with EtOAc. The EtOAc extracts were washed with water, then extracted 4× with 1N NaOH. The aqueous extracts were washed once with EtOAc then acidified and the resulting solid filtered, washed with water and dried to yield 4.65 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OCc2ccccc2)c(-c2ccc3ccccc3c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(O)c(-c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A solution of Intermediate 52 (3.20 g) in a mixture of ethyl acetate (50 ml) and methanol (25 ml) was added with 10% palladium/carbon (98 mg), and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain the title compound (Intermediate 53, 2.39 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>ClCCl>[CH2:40]([O:39][C:37](=[O:38])[NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCOc1ccc(NC(=O)c2cccc(OC)c2)cc1-c1ccnn1C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins To this was added ethyl chloroformate (8.58 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 52.4% yield. LCMS m/z (%)=439 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.07 Hz, 3H), 3.44-3.51 (m, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 3.94-4.21 (m, 5H), 6.38 (d, J=2.53 Hz, 1H), 7.03 (d, J=9.60 Hz, 1H), 7.11 (dt, J=4.67, 2.27 Hz, 1H), 7.36-7.46 (m, 3H), 7.62-7.72 (m, 2H), 7.83 (s, 1H)
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[N:12][C:11]([Br:26])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[Br:26][C:11]1[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]2[NH:1][C:15]3[CH:16]=[C:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:18]=[CH:19][C:14]=3[C:13]=2[N:12]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N=[N+]=[N-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)OC(C)C)ccc12
Yield: 30 %

Procedure:
A solution of methyl 3-azido-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)-isonicotinate (1.0 g, 2 4 mmol) in 1,2-dichlorobenzene (30 mL) was heated under reflux for 5min. After removal of the solvent under reduced pressure the residue was purified by silica gel chromatography (elution with hexane containing 30% EtOAc) to afford 7-isopropyl 4-methyl 2-bromo-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (0.48 g, 1.20 mmol, 50% yield). MS (ESI) m/z 391.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (1H, br. s.), 8.42 (1H, s), 8.33 (1H, d, J=8.24 Hz), 8.01 (1H, d, J=1.22 Hz), 7.91 (1H, d, J=8.24 Hz), 5.22 (1H, quin, J=6.03 Hz), 4.06 (3H, s), 1.39 (6H, d, J=6.10 Hz).
Reaction SMILES: C[O-].[Na+].[Na].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].CO[C:13](=[N:25][C:26]([C:28]1[C:37]2[C:32](=[C:33]([Br:38])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=O)[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.OS(O)(=O)=O>CO.O>[Br:38][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[C:26]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[C:13]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:25]=1
Reactant: N#CCC(N)=O
Reactant: COC(Cc1cccc2ccccc12)=NC(=O)c1cccc2c(Br)cccc12
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1c(Cc2cccc3ccccc23)nc(-c2cccc3c(Br)cccc23)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.3 %

Procedure:
To a stirred solution of sodium methoxide, freshly prepared from sodium (1.5 g, 0.065 mol) in methanol (75 mL), was added cyanoacetamide (4.2 g, 0.050 mol). After 2 minutes, methyl-N-(5-bromo-1-naphthoyl)-2-(1-naphthalenyl)acetimidate (21.6 g, 0.050 mol) was added. The resulting mixture was stirred at room temperature for 15 hours, then heated to reflux for 4 hours. After cooling to room temperature, the mixture was neutralized with H2SO4 (1.8 mL) and diluted with water. The product was collected by filtration, washed with water, and dried in vacuo to give a yellow solid (16.4 g, 71%), which was used without purification.