Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([OH:28])=O)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[CH3:29][S:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([S:30][CH3:29])=[CH:32][CH:33]=2)=[O:28])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Reactant: CSc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CSc1ccc(CNC(=O)c2sc(NC(C)=O)nc2CCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.2 %

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (120 mg), [4-(methylthio)benzyl]amine (45.4 mg), 1-hydroxybenzotriazole (44 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.6 mg) in DMF (2 ml) was stirred at r.t. for 17 hours. The reaction mixture was poured into saturated NaHCO3, and extracted with CHCl3. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/AcOEt (1:1) as an eluent to give tert-butyl (4-{2-[2-(acetylamino)-5-({[4-(methylthio)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate (163.5 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:15][CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCC(c2cccnc2F)CC1
Solvent: O
Solvent: ClCCl
Product: O=C1CCCC(c2cccnc2F)CC1

Procedure:
To a solution of boron trifluoride-diethyl etherate (0.64 g, 4.50 mmol) and 4-(2-fluoropyridin-3-yl)cyclohexanone (0.79 g, 4.09 mmol) in DCM (8 mL) at −25° C. under argon was added (trimethylsilyl)diazomethane (2.25 mL, 5.18 mmol, 2.0 M in hexanes). The reaction was stirred for 2 h at that temperature, water was added, and the mixture was extracted with DCM (2×). The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide mixture (1×), water (1×), saturated aqueous sodium chloride (1×), and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 4-(2-fluoropyridin-3-yl)cycloheptanone. MS (ESI, pos. ion) m/z: 208.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCNCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.57 g of tert-butyl (2-bromoethyl)carbamate (7.0 mmol, 0.7 equivalents) were initially charged in 98.5 ml of acetonitrile, 0.87 ml of 2-methoxyethylamine (750 mg, 10.0 mmol, 1 equivalent) and 3.5 ml of N,N-diisopropylethylamine (2.58 g, 20 mmol, 2 equivalents) were added and the mixture was stirred at 80° C. overnight. The mixture was concentrated and the residue was purified on a silica gel column (mobile phase: dichloromethane/methanol gradient: from 50:1 to 30:1 to 10:1, then dichloromethane/2 N ammonia in methanol: 10:1). This gave 1.69 g (99% of theory; purity about 90%) of the title compound.
Reaction SMILES: [O:1]([CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12](=[O:23])[NH:13][C@@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:1][CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:12](=[O:23])[NH:13][C@@H:14]([CH3:22])[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16]
Reactant: COCCN(CCO[Si](C)(C)C(C)(C)C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCCN(CCO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C

Procedure:
t-Butyl (2S)-2-[3-[2-(t-butyldimethylsiloxy)ethyl]-3-(2-methoxyethyl)ureido]propionate (Compound No. 3-1, 2.79 g) is dissolved in anhydrous tetrahydrofuran (11 ml) under a nitrogen atmosphere. Tetra-n-butylammonium fluoride (7.3 ml) is added to the solution at room temperature with stirring, and the mixture is stirred for one hour. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 2.14 g (quantitatively) of the titled compound (Compound No. 4-1).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]1[N:37]=[C:36](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:35]([F:51])=[CH:34][C:26]=1[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(OC(C)C)(C)C>C(Cl)(Cl)Cl.O>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:36]2[C:35]([F:51])=[CH:34][C:26]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:25]([NH:24][C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])[N:37]=2)[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)CCc1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Yield: 93.8 %

Procedure:
In 1.5 ml of chloroform was suspended 50 mg of 3-aminopyrrolidine dihydrochloride, and 110 mg of triethylamine was added thereto after which the resulting mixture was subjected to reaction at room temperature for 10 minutes. Thereafter, 150 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinyl]acetate was added thereto, and the resulting mixture was subjected to reaction at room temperature for 1.5 hours. Subsequently, to the reaction mixture were added 5 ml of chloroform and 5 ml of water, and the organic layer was separated, washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 110 mg (yield 93.2%) of ethyl 2-[6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 29.
Reaction SMILES: O=[C:2]([CH2:14][CH2:15][CH:16]=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C[O-].[Na+]>CO>[O:17]=[C:16]1[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:2][CH2:14][CH2:15]1
Reactant: COC(=O)CCCCCCCC(=O)CCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCC1=CCCC1=O

Procedure:
A solution of the ester (VI) (10 g, 0.041 mole) in methanol (15 ml) is added dropwise, under nitrogen and stirring at reflux, to a solution of sodium methoxide [prepared from sodium (2.17 g; 0.094 mole) and methanol (280 ml)] At the end of the addition, the mixture is refluxed for 15 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1>[OH-].[Pd+2].[OH-].[OH-].[NH4+].CO>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cc1ccc(CN)cc1
Reaction time: 0.33 h
Yield: 119.3 %

Procedure:
Palladium hydroxide (Pearlman's catalyst, 1.04 g) was added to a solution of conc. aq. ammonium hydroxide:methanol (1:4) (50 mL) in a Parr flask. (4-Cyano-phenyl)-acetic acid methyl ester (1.00 g) was added to the solution. The Parr flask was then shaken for 20 min under hydrogen (50 psi). The reaction mixture was filtered (nylon 66) and the filtrate concentrated in vacuo to yield crude title compound (1.22 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[N:19]=[C:18]([CH:30]([CH3:32])[CH3:31])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:30]([CH3:32])[CH3:31])=[N:19][N:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (86.5 g, 486 mmol) was added in portions to the pyrazole (164 g, 486 mmol, Step A) in DMF (1l) at 0° C. under an atmosphere of N2. This mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was poured into H2O (1 l) and the resulting precipitate was collected and washed with water. The product was dried overnight to give 184.1 g (91%), mp 146°-147° C. (hexanes).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:23]=[C:22]([N:24]([CH3:26])[CH3:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:25][N:24]([CH3:26])[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[N:23]=1
Reactant: CN(C)c1nc(NC2CCN(Cc3ccccc3)C2)nc2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1nc(NC2CCNC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 13 h
Yield: 94.1 %

Procedure:
To a solution of N2-(1-benzyl-pyrrolidin-3-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (3.3 g, 9.5 mmol) in MeOH (33 mL) was added Pd(OH)2 (660 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 13 hr, and stirred at 50° C. for 6 hr. The mixture was filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 1% to 3% MeOH in CHCl3) to give N4,N4-dimethyl-N2-pyrrolidin-3-yl-quinazoline-2,4-diamine (2.3 g, 93%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>C(OCC)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was diluted with diethyl ether, suction filtered and washed with diethyl ether. The precipitate was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[Cl:27]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.N.ClCCl>FC(F)(F)C(O)=O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([Cl:27])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Cl)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reaction time: 0.25 h

Procedure:
2.1 g of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (5 mmol) and 388 mg of trichloroisocyanuric acid (1.67 mmol) are dissolved in 100 ml of trifluoroacetic acid at room temperature. After 15 minutes, ice is added, it is made alkaline with conc. ammonia and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed and the product crystallizes from ethyl acetate/ether, yield 480 mg (21% of theory).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(S(=O)(=O)[C@@H]3CC[C@@H](C(=O)NC4(C#N)CC4)C3)c(Cl)c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,3S)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 1-ethyl-piperazine to afford the desired product as a light yellow oil. MS (EI): 465.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
4-Chloromethylbenzoic acid (20 mmol) was dissolved in 20 ml THF, then 30 ml borane/THF were added. The mixture was stirred for 16 hrs at room temperature, and then quenched with excess methanol. Evaporation yielded about 2.5 g 4-chloromethylbenzyl alcohol 36.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Br
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.48 mmol) and 5-aminoindole (75 mg, 0.57 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-25% EtOAc in hexane), the title compound as a yellow solid. MP 205-207° C. MS (ESI, pos. ion) m/z: 409 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][CH3:20])=[O:15])[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[CH2:24]=O>O1CCCC1>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:24])[CH2:20]3)=[O:15])[CH:8]=2)=[C:4]([F:23])[CH:3]=1
Reactant: CNCCNC(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Reactant: C=O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To 1-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-3-(2-methylaminoethyl)urea (56.8 mg) dissolved in tetrahydrofuran (5 ml) was added paraformaldehyde (59 mg), followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and partitioned between ethyl acetate and 2N aqueous solution of sodium hydroxide. The separated organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (22.4 mg, 38%) as white powder.
Reaction SMILES: Cl.[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5][CH:4]=N1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][C@H:27]4CCCN[CH2:28]4)[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]3[N:25]=[C:24]([NH:26][CH:27]4[CH2:28][CH2:4][CH2:5][CH2:6][N:2]4[C:7](=[NH:8])[NH2:9])[C:23]([F:33])=[CH:22][N:21]=3)=[CH:18][N:17]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:14]2=[N:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCN4C(=N)N)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
To a solution of pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2, 3-13]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added iPr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5-20% MeOH/CH2Cl2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]1(C2C3C(=CC=CC=3)NC(=O)C2)C=CC=CC=1.CI>C1COCC1>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([O:25]CC)=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2c(OC)c(F)c(F)c(N)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Yield: 85.9 %

Procedure:
A solution of ethyl 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (601 mg, 1.55 mmol) and 1M aq. NaOH (4.5 mL) in EtOH (10 mL) was stirred at 50° C. for 1 h. The solvent was removed and the residue was dissolved in water. The solution was acidified to pH 7 with 2M HCl and the resulting precipitate was removed by filtration, washed with water, EtOH and dried to yield 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (480 mg, 85%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26]#[N:27])[CH2:24][CH2:25]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(C#N)CC2)cc1
Agent: BrB(Br)Br
Product: N#CC1(c2ccc(-c3c(O)ccc4[nH]c(=O)c5sccc5c34)cc2)CC1
Yield: 27.6 %

Procedure:
Following General Procedure F, 1-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]cyclopropanecarbonitrile (340 mg, 0.91 mmol) was reacted with tribromoborane (1.3 mL) to afford the desired product (90 mg, 28%) as a light brown solid: ESI MS m/z 359 [C21H14N2O2S+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl.C(OCC)(=O)C>[C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[CH:4][CH:3]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: Nc1ccc(Cl)c2ccccc12
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(Cl)c2ccccc12
Yield: 68 %

Procedure:
To a stirred solution of 1-amino-4-chloronaphthalene (0.70 g, 3.9 mmol) in dichloromethane (50 ml) was added triethylamine (1.0 ml, 7 mmol), followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min the mixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl (100 ml) followed by saturated sodium carbonate (100 ml). The organic phase was separated, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with a mixture of ethyl acetate and heptane, 130 ml, 3:10) to give 0.62 g (67%) of the desired compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.[NH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[CH:19]=1>>[C:24]([C:23]([CH3:27])([CH3:26])[C:20]1[CH:19]=[C:18]([NH:17][C:3](=[O:5])[C:2]([CH3:1])([S:7]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH3:6])[O:22][N:21]=1)#[N:25]
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC1CCOCC1
Reactant: CC(C)(C#N)c1cc(N)on1
Product: CC(C)(C#N)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1

Procedure:
Prepared according to procedure of example 1 starting from 100 mg (0.40 mmol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid (intermediate 2) and 66.4 mg (0.44 mmol) 2-(5-amino-isoxazol-3-yl)-2-methyl-propionitrile (intermediate 7).