Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH:23]3[CH2:22][CH2:21][N:20]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:25][CH2:24]3)=[CH:34][CH:33]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1(NC(=O)c2ccc(C3CCN(C4CCCC4)CC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.74 mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74 mmol), HOBT (0.74 mmol), WSCD (0.74 mmol) and triethylamine (0.74 mmol) are dissolved in DMF (5 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234° C., Rf=0.34 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1([S:15]([C:18](=[CH:23]OCC)[C:19](OC)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[OH:20][C:19]1[C:5]2[C:3](=[C:2]([F:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:23][C:18]=1[S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1F
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1cnc2c(F)cccc2c1O
Temperature: 260 °C
Reaction time: 6 h
Yield: 3.3 %

Procedure:
2-Fluoroaniline 7(1) (3.82 g, 0.0344 mol) and methyl 2-phenylsulfonyl-3-ethoxy-acrylate 7(2) (9.59 g, 0.0355 mol) were mixed together in biphenyl ether (21.5 ml). The mixture was stirred in an opened flask for 6 h at 250-270° C. Ethanol was distilled during the first 30 min. After the reaction was completed (LCMS control) the mixture was cooled, the formed solid was filtered off, dissolved in ethanol and solution was boiled with charcoal. After filtration from charcoal ethanol was evaporated, the residue was subjected to chromatography on silica, eluent—gradient of solvent system CHCl3:ethyl acetate=from 10:1 to 5:1. The residue after evaporation of fractions, comprising the final product was washed with ether, it gave 345 mg (3.3%) of 4-hydroxy-3-phenylsulfonyl-8-fluoroquinoline 7(3).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH2:17])[CH:13]=[CH:12]2)[CH2:3][CH:4]=[CH2:5].B.C1C[O:22]CC1.[OH-].[Na+]>OO>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:22])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: C1CCOC1
Reactant: C=CCC(C)Oc1cccc2ccc(N)nc12
Agent: B
Agent: OO
Agent: [Na+]
Product: CC(CCCO)Oc1cccc2ccc(N)nc12
Temperature: 25 °C

Procedure:
To a 100 mL round bottom flask containing 1.33 g (5.83 mmol) of 8-(1-methyl-but-3-enyloxy)-quinolin-2-ylamine was added 30 mL of a 1M solution of BH3/THF via syringe. Following the addition, the flask was fitted with a reflux condenser and the solution heated to reflux under N2 for 6 h. The reaction mixture was then allowed to cool to room temperature and the volatiles were removed in vacuo. The residue was dissolved in Et2O. Following the addition of 2.25 g (56.2 mmol) of solid NaOH, the mixture was placed in an ice bath. The flask was then fitted with a dropping funnel and 10 mL of 20% aqueous H2O2 was added dropwise with stirring. The funnel was then replaced with a reflux condenser and the mixture heated to reflux with stirring overnight. The resulting suspension was allowed to cool to room temperature and was filtered through a fritted funnel. The ethereal layer was separated, washed thoroughly with 1 M NaHSO4, dried over anhydr. Na2SO4 and evaporated in vacuo. The resulting crude material was purified by silica gel column chromatography (5–25% MeOH/CH2Cl2) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 (d, 1H), 7.16 (m, 1H), 7.03 (m, 1H), 6.97 (m, 1H), 6.73 (d, 1H), 6.33 (s, 1H), 4.62 (m, 1H), 4.46 (m, 1H), 3.44 (m, 2H), 1.76 (m, 1H), 1.59 (m, 3H), 1.27 (d, 3H); MS (DCI/NH3) m/z 247 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[Br:19][C:20]1[O:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[O:21][CH:22]=[C:23]([C:25]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1coc(Br)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(Br)n1
Yield: 12.4 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (741 mg, 2.82 mmol) and 2-bromooxazole-4-carboxylic acid (850 mg, 3.41 mmol). The product was purified by Flash-chromatography. Yield 12.4%. 1H-NMR (400 MHz; CDCl3): δ 1.20 (d, 3H), 4.18-4.47 (m, 2H), 4.51-4.65 (m, 1H), 6.64 (d, 1H), 7.48 (d, 1H), 7.72 (dd, 1H), 7.92-7.99 (m, 3H), 8.21 (s, 1H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Cl:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][Cl:12].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1COCC1>[Cl:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][Cl:12])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=P(Cl)(Cl)N(CCCl)CCCl

Procedure:
Phosphorous oxychloride (0.15 mol) in 100 ml. THF are mixed dropwise at 10° C. with bis-chloroethylamine (0.1 mol) in 100 ml. THF and triethylamine (0.15 mol). After ending of the reaction (TLC verification), triethylamine hydrochloride is filtered off and the filtrate, after the addition of 50 ml. toluene, evaporated. The oily residue is immediately further reacted.
Reaction SMILES: [F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>ClCCl>[F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: CC(F)(F)C(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(F)(F)C(C)(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 1.55 g (9.86 mmol) 3,3-difluoro-2,2-dimethylbutanoic acid in 5 ml of dry dichloromethane was added 3.45 ml (39.5 mmol) of oxalyl chloride. The mixture was stirred at room temperature for 20 hours then solvent and excess reagent removed by distillation followed by addition of carbon tetrachloride and distillation of the solvent. The cooled 3,3-difluoro-2,2-dimethylbutanoyl chloride thus formed was dissolved in 8 ml of dry pyridine and added to a mixture of 2.15 g (4.93 mmol) of [1S-[1α(4R*,6R*),2α, 6β,8β,8aβ]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one, 0.35 g of 4-pyrrolidinopyridine and 10 ml of dry pyridine. The mixture was heated at 50° overnight then cooled and quenched by the addition of ice chips. The mixture was taken up in diethyl ether and washed successively with water, dilute sulfuric acid and saturated sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane/dichloromethane/ethyl acetate (25:25:50) to give 0.314 g of 3,3-difluoro-2,2-dimethylbutanoic acid, [1S-[1α,3α,7β,8β (2R*,4R*)8aβ]]-8-[2[tetrahydro-4-[[(1,1-dimethylethyl]dimethylsilyl]oxy]-6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[I:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]Br)=[CH:25][CH:24]=1>>[I:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCCCCCCCCCCCI
Reactant: BrCCc1ccc(I)cc1
Product: CCOC(=O)CCCCCCCCCCCCCCCCCc1ccc(I)cc1

Procedure:
Another approach is shown in SCHEME III. It can be described as C16+IPhC2=IPhC18. The C16 fragment 43 originates from relatively inexpensive 16-hexadecanolactone 31. Lactone cleavage with trimethylsilyl iodide in the presence of ethanol results in ethyl 16-iodohexadecanoate 43. Iodoester 43 is coupled with organozinc reagent 44 made from 2-(p-iodophenyl)ethyl bromide to give ester 37 which has all 18 carbons chain required for NM404. Ester 37 is converted into 18-(p-iodophenyl)octadecanol 12 in two steps as shown in SCHEME III.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:18][O:17]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-n2ccc(OCC3CO3)n2)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(COc1ccn(-c2ccc(Cl)c(Cl)c2)n1)CN1CCOCC1
Yield: 37.3 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-3-(oxiran-2-ylmethoxy)-1H-pyrazole (0.23 g, 0.82 mmol), morpholine (72 mg, 0.82 mmol), potassium carbonate (0.34 g, 2.47 mmol) and sodium iodide (123 mg, 0.82 mmol) in dimethylformamide (6 ml) was refluxed 8 hrs and the solvent evaporated in vacuo. To the crude residue was added water and dichlorometane, the aqueous solution extracted several times with dichlorometane and the combined organic phases washed with water, dried over sodium sulphate, filtered and evaporated to dryness in vacuo. The crude dark oil obtained, 296 mg, was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether 1:1 to 1:0 and ethyl acetate/CH3OH 9:1) yielding 114 mg of 1-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)-3-morpholinopropan-2-ol.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH3:19]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([NH2:19])=[O:18])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Reactant: N
Product: CCc1cc(-c2ccc(C(N)=O)o2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-furan-2-carboxylic acid and ammonia to afford the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:16]=3[F:23])=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>CS(C)=O.CCOC(C)=O.O>[CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=3[F:23])=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2nc3cc(Cc4ccccc4)ccc3[nH]2)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2nc3cc(Cc4ccccc4)ccc3[nH]2)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of (4-(5-benzyl-1H-benzo[d]imidazol-2-yl)-3-fluorophenyl)methanol (0.055 g, 0.17 mmol) and triethylamine (0.12 mL, 0.83 mmol) in 1.5 mL 1:1 DCM/DMSO under nitrogen at 0° C. was added a solution of SO3*py (0.13 g, 0.83 mmol) in 0.75 mL DMSO. The reaction was allowed to stir for 2 h and was then diluted with EtOAc and water. The organic layer was washed 1× water, 1× brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ISCO, 12 g, 0-40% EtOAc/hexanes, to give 4-(5-benzyl-1H-benzo[d]imidazol-2-yl)-3-fluorobenzaldehyde as a light yellow oil. MS (ESI) m/z: Calculated: 330.1; Observed: 331.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClCCCl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
2-Aminothiazole (100 mmol) was suspended in 1,2-dichloroethane (200 mL) and pyridine (100 mmol) was added. The mixture was added portion wise to a suspension of 4-nitro benzoic acid chloride (150 mmol) in 1,2-dichloroethane (500 mL) and stirred at 60° C. over night. The reaction mixture was cooled and filtered. The filtrate was washed with 1,2-dichloroethane and dried in vacuo to give 4-nitro-N-thiazol-2-yl-benzamide.
Reaction SMILES: [C:1]1([C:7](=[O:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OCC)(=O)C>[C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
60.1 mg (0.50 mmol) of 1-phenylethanone (32), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 6 hours at 800 rpm (reversed every 30 minutes). After the lapse of 6 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 42.8 mg (0.35 mmol) of 1-phenylethanol (33). The yield was 70%. The reaction is expressed by the following scheme.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNc1ccc(F)cc1[N+](=O)[O-]
Yield: 74.7 %

Procedure:
A mixture of 2,5-difluoronitrobenzene (54.6 g, 343 mmol), glycine methyl ester hydrochloride (47.3 g, 374 mmol) and triethylamine (114.5 mL, 818 mmol) was heated at 65° C. (internal temperature) in THF (1500 mL) over a 3 night period. Additional glycine methyl ester hydrochloride (30 g) and triethylamine (20 mL) were added and the heating continued for a further 2 nights. The mixture was cooled, filtered and evaporated to dryness. The residue was treated with 5M hydrochloric acid and the orange solid was filtered off, washed well with water (total ˜2 L) and dried under vacuum to give the product (58.5 g). The product was then extracted with ethyl acetate (600 ml total), filtered and evaporated. The residue was slurried with water (1 L), filtered and dried to give product (40 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:1][C:2]1[CH:7]=[C:6]([I:10])[C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(F)cc(Br)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(4-bromo-2-fluorophenyl)amine (6 g) was dissolved in ethanol (200 mL), silver sulfate (10.8 g) was added and then iodine (8.8 g) was added in small portions. After the addition was complete, the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and evaporated to leave a dark oil which was taken up in EtOAc, washed with saturated sodium thiosulphate (100 mL×2), sodium carbonate solution (100 mL×2) and water. The organic layer dried over anhydrous Na2SO4 and evaporated. The crude product was purified by column chromatography to give (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (8.6 g) as a yellow solid. MS (ES): C6H4BrFIN requires 315; found 315.9 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[CH:15]=[C:16]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)[CH:17]=[C:18]3[C:22]=1[NH:21][N:20]=[CH:19]3)=[CH:10]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:30][C:26]1[N:25]=[C:24]([NH:23][C:16]2[CH:17]=[C:18]3[C:22](=[C:14]([C:11]4[NH:12][C:13]5[C:9]([CH:10]=4)=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:3][OH:2])[CH:15]=2)[NH:21][N:20]=[CH:19]3)[CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)c1cccc2cc(-c3cc(Nc4ccnc(N)n4)cc4cn[nH]c34)[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccc(Nc2cc(-c3cc4cccc(CO)c4[nH]3)c3[nH]ncc3c2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 30.2 %

Procedure:
2-[5-(2-Amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indole-7-carboxylic acid methyl ester (Preparation #F.8.1, 0.100 g, 0.000250 mol) was added to a solution of lithium aluminum hydride in tetrahydrofuran (1.0M, 1.0 mL) at about 0° C. in 3 portions. Additional THF (1.0 mL) was added after about 10 min., and after about 40 min, the mixture was allowed to warm to ambient temperature. After about a further 60 min, lithium aluminum hydride in THF (1.0M, 1 mL) was added. About 16 hours later, the mixture was quenched with water and neutralized with a saturated aqueous solution of ammonium chloride. The mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was further extracted with EtOAc, and the combined organics were dried over anhydrous MgSO4 and concentrated to yield {2-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-1H-indol-7-yl}-methanol (28 mg, 30% yield); LC/MS Rt (Method e) 0.8 min; m/z (M−H)− 370.5.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1C)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(C)cccc2c1=O
Yield: 98.1 %

Procedure:
Ethyl 2-butyryl-3-(2-methylphenylamino)acrylate (66 g, 0.24 mol) was added in portions to boiling diphenyl ether (500 ml), then heated at reflux for 1.5 hours. After partial cooling, the mixture was poured into high boiling petroleum ether. Filtration and washing with petroleum ether gave 3-butyryl-8-methyl-4(1H)-quinolone (54 g) as a pale solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][N:39]([CH2:41][CH2:42][C:43]#[N:44])[CH:40]=2)O1>>[C:43]([CH2:42][CH2:41][N:39]1[CH:40]=[C:36]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([CH:18]5[CH2:19][CH2:20][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:22][CH2:23]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:37]=[N:38]1)#[N:44]
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Product: N#CCCn1cc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)cn1

Procedure:
2-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamide (111 mg, 0.259 mmol) and 3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-propionitrile (128 mg, 0.518 mmol) were reacted in an analogous manner to Example 881A. The resulting crude product was purified by ISCO chromatography (amine capped silica gel) with a gradient of 50-100% EtOAc in hexanes-30% MeOH in EtOAc (41 mg, 34%). LCMS=470.0 (M+H), HPLC rt=1.825 min, 95% purity. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.22 (bs, 1H), 7.14 (bs, 1H), 7.07 (d, J=4.3 Hz, 1H), 6.91 (d, J=4.3 Hz, 1H), 4.48 (t, J=6.4 Hz, 2H), 3.16 (t, J=6.4 Hz, 2H), 2.92 (d, J=10.5 Hz, 2H), 2.88 (s, 2H), 2.47-2.44 (m, 1H), 2.18-2.13 (m, 2H), 1.76-1.74 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1c(F)cncc1F)c1c(F)cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc(F)c1C(Cl)=Nc1c(F)cncc1F
Temperature: 25 °C

Procedure:
A mixture of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide (10.81 g, 36.4 mmol) in thionyl chloride (95 mL) was heated under reflux for 3 days under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) to afford the title compound as a yellow/pale brown solid (12.05 g, quantitative). LCMS (Method D): RT=3.64 min, m/z: 316 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:24]=[CH:23][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=3[CH:8]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCBr)cc21
Reactant: C1CNC1
Product: O=S1(=O)N=C(c2ccc(Cl)cc2)c2ccc(OCCCCN3CCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxide and Azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxide, MS: 405 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](=[O:29])[N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: C1CCNC1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCCC1
Yield: 77.6 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.53 mmol) was reacted with pyrrolidine (0.44 ml, 5.3 mmol) to give the title compound as a white solid (210 mg, 77%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.08 (br s, 1H); Mass spectrum 511.