Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(OC)OC
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
22.8 g (0.097 mol) of N-benzyloxycarbonyl-L-valinal were dissolved in 55 ml of dry methanol. The solution was treated with 10.8 g (0.102 mol) of trimethyl orthoformate and 0.3 g of toluene-4-sulphonic acid and the mixture was left to stand at room temperature for 16 hours. The solvents were removed by evaporation, the residue was dissolved in 150 ml of ethyl acetate and the solution was washed with 5% sodium bicarbonate solution and then with brine. After drying over magnesium sulphate and filtration, the solvent was removed by evaporation to yield 24.5 g (90%) of N-benzyloxycarbonyl-L-valinal dimethyl acetal as an oil; Rf-value [hexane/ethyl acetate (2:1)]: 0.69.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Li+].[OH-].C1COCC1.CO.Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(COC(=O)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccco3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 36.5 %

Procedure:
4-Methoxybenzyl 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-2a) (750 mg, 1.4 mmol) was stirred a 2/2/1 mixture of aqueous 2N LiOH/THF/MeOH (45 mL) at ambient temperature for 3 hours. The solution was acidified with aqueous 1N aq HCl to a pH of ˜3 (ca. 100 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (9 mL) and purified by reverse phased HPLC (5-95% ACN in H2O gradient: 40 minutes) in three-3 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in absolute ethanol and evaporated (4×, 20 mL) to provide pure 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (205 mg, 36%) as a white solid. M.p. 151-152° C. 1H NMR (DMSO-d6, 400 MHz): 3.71 (s, 3H), 4.24 (s, 2H), 4.27 (s, 2H), 6.14 (d, 1H, J=3.2 Hz), 6.26 (m, 1H), 6.87 (d, 2H, J=9.2 Hz), 7.14 (d, 2H, J=8.8 Hz), 7.41 (s, 1H), 7.89 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8.4 Hz), 13.48 (bs, 1H). MS 400 (M−H).
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH:7]([CH3:16])[CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:16])[N:6]=1
Reactant: CC(NC(=O)c1ccccc1I)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of amide 3a, 9.5 g, 24.9 mmol) and P2O5 (44 g) in o-dichlorobenzene (150 mL) was refluxed for overnight. After it was cooled to room temperature, it was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 300 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×50 mL). The aqueous layer was cooled to 0° C. and made to pH>11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.68 g, 80%). mp 111-112° C. 1H NMR (CDCl3) d 2.67 (s, 3 H, CH3), 7.00-7.05 (m, 1 H, aromatic), 7.26-7.52 (m, 6 H, aromatic), 7.65 (d, J=8.1 Hz, 1 H, aromatic), 7.88 (d, J=8.1 Hz, 1 H, aromatic). 13C NMR (CDCl3) d 24.05 (q, CH3), 97.82 (s, =CI--, aromatic), 118.26 (d, aromatic), 124.45 (s, aromatic), 125.98 (d, aromatic), 126.77 (d, aromatic), 127.70 (d, aromatic), 129.43 (d, aromatic), 129.79 (d, aromatic), 129.92 (d, aromatic), 136.73 (s, aromatic), 138.78 (d, aromatic), 143.74 (s, aromatic), 150.24 (s, aromatic), 161.34 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.77; H, 3.51; N, 3.96.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:10]=2)=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: Brc1cnc2[nH]c(-c3ccc(NCc4ccccc4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)aniline (0.289 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[C:6]4[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (example 1, intermediate C) (1.6 g, 6 mmol), triethylamine (0.64 mL, 5 mmol) in 1,2 dichloroethane (27 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.9 g, 9 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 2.3 g (5.1 mmol, 100% yield) of a off-white solid. MS (m/e): 446.3 (M+H+).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:3][CH:2]=1.C(OCC)(=[O:32])C.O>CO.O>[C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([CH2:8][CH2:9][C:10]2[N:28]=[C:13]3[CH:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:26])([F:27])[F:25])[CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[O:32])=[CH:3][CH:2]=1
Reactant: Cc1ccc(SCCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)CCc2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-p-Tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (8.8 g) was dissolved in a mixed solvent of methanol-water (2:1 v/v) (300 ml). Sodium periodide (6.78 g) was added under cooling with an ice water bath, and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (8.87 g). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>ClCCl>[CH3:4][C:3]1([CH3:6])[O:5][C:13](=[O:14])[NH:1][C@H:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC1(C)OC(=O)N[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of C2 (38.8 g, 235 mmol) in dichloromethane (1000 mL) was treated with carbonyldiimidazole (45.6 g, 281 mmol) and heated at reflux for 2 hours. The reaction mixture was cooled to 25° C., quenched with 1 N hydrochloric acid (560 mL), and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate and concentrated, and the resultant residue was purified by trituration with 4:1 hexanes:ethyl acetate, followed by chromatography on silica gel (gradient: 9:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide C3 as a white solid. Yield: 24.7 g, 55%. MS (APCI) m/z 192.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, s), 1.58 (3H, s), 4.62 (1H, s), 5.53-5.60 (1H, br s), 7.20-7.39 (5H, m).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.O=[C:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>Cl>[CH2:22]([C:16]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:23]
Reactant: CCc1cccc2c(CCO)c[nH]c12
Reactant: CCC(=O)CC(=O)OC
Agent: Cl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 27.5 °C
Reaction time: 7 h
Yield: 76.9 %

Procedure:
To a solution of 7-ethyltryptophol (12.0 g) in 1-butanolic hydrogen chloride (5% w/v, 100.0 ml), methyl 3-oxopentanoate (9.1 g) was added in one lot, at 25° C. The reaction mixture was stirred at 25-30° C. for 7 hours. The reaction mixture was extracted with hexane (100.0 ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the titled compound (14.7 g, 79%), m.p. 128-130° C.; purity: 96.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.FC1C=CC(C2C(CO[C:38]3[CH:39]=[C:40]([C:43](O)=O)[NH:41][N:42]=3)=C(C)ON=2)=CC=1>>[N:42]1([NH:41][C:20]([C:17]2[NH:18][N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])[CH:16]=2)=[O:22])[CH2:43][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)[nH]n1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN2CCCC2)[nH]n1
Yield: 39 %

Procedure:
As described for example 10b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid (38 mg, 0.12 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid, was converted, to the title compound (18 mg, 39%) which was obtained as a white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([CH2:17][C:18]#[N:19])=O>C(O)C>[NH2:19][C:18]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[CH:17]=1
Reactant: NNC(N)=O
Reactant: N#CCC(=O)c1ccco1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccco2)cc1N
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a stirred solution of 5.5 g of semicarbazide hydrochloride in 100 ml of absolute ethyl alcohol is added 3.0 g of sodium methoxide at room temperature. The reaction mixture is stirred for 30 minutes and 6.0 g of 2-furoyl acetonitrile is added. The reaction mixture is heated at reflux for 1 hour and concentrated in vacuo to a residue. The residue is suspended in water, filtered and dried to give 6.0 g of the desired product as a solid, m.p. 145° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15](OCC)=[O:16])[CH:11]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:16])[CH:11]=1
Reactant: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Cyclopropylamine (1.86 mL) was added to 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169e, 1.6 g) in THF (24 mL) under nitrogen at room temperature and isopropylmagnesium chloride (5.28 mL of a 2M solution in THF) was then added dropwise over 10 min. The resulting solution was stirred at 75° C. for 16 h. After cooling to room temperature, the solution was acidified with 2M HCl and extracted into dichloromethane. The organic fractions were concentrated in vacuo to give the subtitle compound (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][N:16]=1)[N:13]=[CH:12][C:11]([C:21]#[N:22])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: NCc1ccccc1
Product: N#Cc1cnc2cnc(NCc3ccccc3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 54 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with benzylamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.051 g, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 4.5 (d, J=6.3 Hz, 2 H) 7.0 (s, 1 H) 7.2 (t, J=7.2 Hz, 1 H) 7.3 (m, 5 H) 7.5 (m, 2 H) 7.6 (dd, J=6.6, 2.5 Hz, 1 H) 8.3 (s, 1 H) 8.9 (s, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][CH2:4][NH:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:14][CH3:15])=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:17]1.[Cl:29][C:30]1[C:43]([N:44]=[C:45]=S)=[C:42]([Cl:47])[CH:41]=[CH:40][C:31]=1[CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].CC(C)N=C=NC(C)C>CC#N>[F:28][C:2]([F:1])([F:27])[CH2:3][CH2:4][NH:5][C:6]([C:7]1[C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[CH2:17]2)=[CH:9][C:10]2[N:14]([CH3:15])[C:45]([NH:44][C:43]3[C:42]([Cl:47])=[CH:41][CH:40]=[C:31]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]=3[Cl:29])=[N:13][C:11]=2[CH:12]=1)=[O:26]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(3,3,3-trifluoro-propyl)-2-[3-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoic acid amide (93 mg, 0.22 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (71 mg, 0.22 mmol), DIC (35 μL) and MeCN (2.0 mL).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:23])[CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Reactant: C1CCNC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1)N1CCCC1
Yield: 47 %

Procedure:
3-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (31 mg) was coupled to pyrrolidine as in General Procedure 8 to give the title compound as a yellow solid (47% yield). LCMS: m/z=413.30 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 1.92 (2H, m), 2.02 (2H, m), 3.36 (1H, m), 3.40 (2H, t, J=6.6 Hz), 3.62 (2H, t, J=6.9 Hz), 4.49 (2H, s), 4.91 (1H, s), 5.36 (2H, s), 7.29 (1H, m), 7.37 (2H, d, J=1.8 Hz), 7.39 (2H, s), 7.49 (1H, s), 7.52 (3H, s), 7.53 (1H, d, J=1.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=3)[N:9]=[N:10][C:11]=2[C:16]=1[OH:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2nnc3c(O)cccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(O)c(Cl)ccc32)cc1

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-ol (0.984 g, 3.85 mmol) at 0° C. in THF (15 mL) was added 1N NaOH (3.85 mL, 3.85 mmol). The resulting mixture was then stirred for several minutes, after which N-chloro-succinimide (0.515 g, 3.85 mmol) was added in one portion. The stirred reaction mixture was quenched after 5 minutes at 0° C. with aqueous ammonium chloride (25 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2O, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2×100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product. 1H NMR (DMSO d6) δ 11.61 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 5.84 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:48]2[C:43](=[CH:44][N:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:48]5[C:43](=[CH:44][N:45]=[CH:46][CH:47]=5)[NH:42][CH:41]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: Brc1c[nH]c2cnccc12
Product: CN(C)C1CCN(Cc2cc3nc(-c4c[nH]c5cnccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 3-bromo-1H-pyrrolo[2,3-c]pyridine were reacted to give 216. LCMS m/z: 478.6 (MH+)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1.CC(C)([O-])C.[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:33]=[CH:32][C:31]3[C:27](=[C:28]([CH3:37])[N:29]([CH:34]4[CH2:36][CH2:35]4)[N:30]=3)[CH:26]=2)[C:21](=[O:38])[CH:20]=1.O>CC(N(C)C)=O>[CH:34]1([N:29]2[C:28]([CH3:37])=[C:27]3[C:31]([CH:32]=[CH:33][C:25]([N:22]4[CH:23]=[CH:24][C:19]([O:9][CH2:8][C:5]5[CH:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[S:7][CH:6]=5)=[CH:20][C:21]4=[O:38])=[CH:26]3)=[N:30]2)[CH2:36][CH2:35]1
Reactant: Cc1c2cc(-n3ccc(Cl)cc3=O)ccc2nn1C1CC1
Reactant: OCc1csc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)ccc2nn1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of [5-(trifluoromethyl)thiophen-3-yl]methanol (100 g) in DMA (1363 ml) was added potassium tert-butoxide (61.3 g) at 5° C., and the mixture was stirred at the same temperature for 30 min. To the obtained mixture was added 4-chloro-1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (136.5 g), and the mixture was stirred at an inside temperature of 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature, water (1.4 L) was added, and the obtained suspension was stirred overnight. The precipitated solid was collected by filtration, and washed with water (2.8 L), ethanol (540 ml) and diisopropyl ether (500 ml) to give the title compound (168.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[C:13](C)=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[OH:16])=[O:7].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:15][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[CH:10][C:9]=1[OH:16])=[O:7]
Reactant: COC(=O)CCC(=O)c1c(C)cc(O)cc1O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(OC2CCCCO2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a mixture of 4-(2,4-dihydroxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (1.0 g, 4.20 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (0.38 mL, 8.40 mmol) and pyridium p-toluenesulfonic acid (0.010 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-[2-hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-oxo-butyric acid methyl ester (1.1 g, 81%). 1HNMR (400 MHz, CDCl3): 12.40 (s, 1H), 6.95 (s, 1H), 6.90 (s, 1H), 5.90 (br s, 1H), 3.27 (t, J=7.8 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.30 (s, 3H).
Reaction SMILES: CS([CH2:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)(=O)=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1COCC1>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)[CH3:17]
Reactant: CCNCC
Reactant: CS(=O)(=O)CCc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc2cc[nH]c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 6-(2-(Methanesulfonyl)ethyl)-indole (107 mg, 0.45 mmol) and diethylamine (0.4 ml) in 2 ml of THF was stirred at 65° C. overnight. The reaction mixture was concentrated in vacuo and passed through a silica gel column, eluting with 2% 2M ammonia/methanol in dichloromethane, to give the title compound, 42 mg (43% yield).