Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[C:14]([Br:28])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(Br)c2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (418 mg, 1.13 mmol), N-bromosuccinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230–400 mesh, 2.51 g) and methylene chloride (70 mL) was stirred at room temperature for 16 h. Solvents were removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3) as eluent to afford the title compound. 1H-NMR (CD3COCD3, 500 MHz) δ 10.71 (s, 1H), 7.35–7.28 (m, 6H), 7.21 (s, 1H), 6.75 (d, J=7.5 Hz, 1H), 5.06 (d, 12.5 Hz, 1H), 5.02 (d, J=12.5 Hz, 1H), 4.56–4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=14.0, 5.0 Hz, 1H), 3.03 (dd, J=14.0, 10.0 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7, 128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; Mass spec. 448.03 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH3:8])[CH2:5][CH2:4][N:3]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[C:18]([F:19])([F:21])[F:20])[C@H:2]1[CH3:1]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H]1NCC[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)cc2C(F)(F)F)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (397 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless oil (yield: 220 mg, yield: 55%).
Reaction SMILES: ClC1C=CC([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12](CC4C=C(C=CC=4)C(O)=O)[C:11]3=[O:29])[CH2:9]2)=CC=1.ClC1C=CC([C@H]2[C@@]3(C4C(=CC=CC=4)N(CC4C=C(C=CC=4)C(O)=O)C3=O)C2)=CC=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N1CCCCC1>CN(C=O)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([CH2:9][CH2:8]2)[C:11]1=[O:29]
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C12CC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(((1S,2R)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid and 3-(((1R,2S)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid (prepared according to Scheme 1) (60 mg, 0.15 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (44 mg, 0.225 mmol 1.5 mmol), anhydrous 1-Hydroxybenzotriazole (HOBt) (31 mg, 0.225 mmol) and piperidine (15 mg, 0.18 mmol) were dissolved in DMF. The mixture was stirred at room temperature for 14 hours. (1R,2S) and (1S,2R)-2-(4-chlorophenyl)-1′-(3-(piperidine-1-carbonyebenzyl)spiro[cyclopropane-1,3′-indolin]-2′-one were purified by preparative HPLC as a white solid (42 mg, 60%). LC/MS m/e calcd. for C29H27ClN2O2: 470, observed (M+H)+: 471.2 1H NMR (400 MHz, MeOD-d4) δppm 1.41 (br. s., 2 H) 1.67 (br. s., 4 H) 2.19-2.30 (m, 2 H) 3.28 (br.s., 2 H) 3.30 (s, 1 H) 3.69 (br. s., 2 H) 5.14 (s, 2 H) 6.11 (d, J=7.33 Hz, 1 H) 6.74 (t, J=7.20 Hz, 1 H) 6.91 (d, J=7.83 Hz, 1 H) 7.03-7.15 (m, 1 H) 7.20-7.28 (m, 2 H) 7.28-7.38 (m, 4 H) 7.43-7.57 (m, 2 H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:21]C)=[N:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:8]1[C:9]([OH:21])=[N:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cnc(OC)c(Cc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCc1cnc(O)c(Cc2ccccc2)c1
Yield: 37.6 %

Procedure:
A mixture of 240 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine, 2.5 ml of 1,2-dichloroethane and a solution of 1.0 M boron tribromide in 0.39 ml of dichloromethane was stirred at 50° C. for 8 hours. Water and silica gel were added to the reaction solution, and the solvent was removed. The residue was subjected to silica gel column chromatography using 75% ethyl acetate/hexane, to give 86 mg of the target compound.
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]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:33]1([NH:39][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
A mixture of 0.100 g (0.22 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-methoxy-benzoic acid (I-22), 0.033 g (0.33 mmole) of cyclohexylamine, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water (gradient, 20:80-100:0) to give 0.013 g of N-cyclohexyl-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-methoxy-benzamide (I-27) as a white solid.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30].CO>CC(C)=O.O.ClCCl>[C:29]([O:32][CH2:33][C:34]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)cc2)C(=O)O1
Temperature: 1.5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydrogen carbonate (1.89 g) was added to a stirred solution of Example 2 (1.92 g) in a mixture of acetone (25 ml) and water (12.5 ml), and the mixture cooled to 0-3° C. Acetoxyacetyl chloride (1.23 g, 0.97 ml) was added dropwise over 5-10 mins. and the reaction mixture was stirred at 0-5° C. for 30 minutes then allowed to warm to ambient temperature over 1 hour. TLC (10% methanol in dichloromethane) showed complete reaction. The reaction mixture was diluted with water and extracted well with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The title compound crystallized during evaporation of the solvent and was triturated with ether (yield=1.70 g, 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccccn1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1cccc(-c2ccccn2)c1
Temperature: 90 °C

Procedure:
2-Bromopyridine (2.00 mL), 3-aminophenylboronic acid (5.40 g) and palladium tetrakistriphenylphosphine (1.2512 g) were added to a mixture of 130 mL of dimethoxyethane and 32 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (300 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 2.75 g of 3-(pyridin-2-yl)benzenamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[NH:8][N:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[I:12]I.[OH-].[K+].S([O-])(O)=O.[Na+]>CN(C)C=O.O>[I:12][C:6]1[C:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:10][C:9]=2[NH:8][N:7]=1
Reactant: CC1(C)CCc2cn[nH]c2C1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCc2c(I)n[nH]c2C1
Reaction time: 4 h
Yield: 23 %

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml) under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr. Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran (250 ml) was added dropwise over about 1 hr, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated and extracted with 2 N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained 4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux over about 1 hr, and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To a solution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole in N,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium hydroxide (121 g, 1.8 mol) at room temperature, and the mixture was stirred for about 4 hr. Then, under ice-cooling, an aqueous solution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise. Water (2 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, hexane (350 ml) was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).
Reaction SMILES: [ClH:1].Cl.CC1N=C([C:9]2[C:14]([S:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH3:17])=[CH:13][N:12]=[C:11]([NH2:24])[C:10]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)SC=1.[CH3:32][C:33]1[N:34]=[C:35](NC2N=CC(SCCC(OC)=O)=CC=2OC2C=CC=CC=2)[S:36][CH:37]=1.CC([O-])(C)C.[K+].BrC(C1C=CC=CN=1)C>>[ClH:1].[CH3:32][C:33]1[N:34]=[C:35]([NH:24][C:11]2[C:10]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][C:14]([S:15][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH3:17])=[CH:13][N:12]=2)[S:36][CH:37]=1
Reactant: Cc1csc(-c2c(SC(C)c3ccccn3)cnc(N)c2Oc2ccccc2)n1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Agent: CC(Br)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Product: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Oc2ccccc2)n1
Yield: 30.8 %

Procedure:
Preparation of N-(4-methylthiazol-2-yl-3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-amine dihydrochloride: Following the procedure in Example 16, methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.325 g, 0.809 mmol), 1M potassium 2-methylpropan-2-olate (2.83 mL, 2.83 mmol), and 2-(1-bromoethyl)pyridine (0.151 g, 0.809 mmol) were reacted to provide N-(4-methylthiazol-2-yl)-3-phenoxy-5-(1-(pyridin-2-yl)ethylthio)pyridin-2-amine hydrochloride (0.114 g, 30.8%) after reverse phase purification and HCl salt formation. 1H NMR (d6-DMSO) δ 8.58 (d, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.58 (d, 2H), 7.45 (t, 2H), 7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.79 (s, 1H), 4.67 (q, 1H), 2.28 (s, 3H), 1.62 (d, 3H); Mass spectrum (esi) m/z=421.1 (M+H-2HCl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[N:25]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[N:26]=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:32]4[CH:31]=[CH:30][C:29]([N:25]5[N:26]=[N:27][CH:28]=[N:24]5)=[CH:34][CH:33]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-n2ncnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-n5ncnn5)cc4)ncnc32)CC1
Yield: 19.2 %

Procedure:
4-[4-(4-Tetrazol-2-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (16 mg, 19%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-(2H-tetrazol-2-yl)phenol (ChemBridge Corporation, San Diego, Calif., USA; 29 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:23][C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][C:82]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:83]=1[SH:89]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:81][C:82]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:83]=1[S:89][C:2]1[CH:3]=[C:4]([O:23][C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3cccnc3C)n2)CC1
Reactant: Cc1cccc(C)c1S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4c(C)cccc4C)cc3Oc3cccnc3C)n2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
1-(4-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.10 g, 0.20 mmol), xantphos (0.059 g, 0.10 mmol), K3PO4 (0.11 g, 0.53 mmol), and Pd2dba3 (0.047 g, 0.051 mmol) were diluted in degassed toluene (2 mL). 2,6-dimethylbenzenethiol (0.041 mL, 0.31 mmol) was added and the reaction stirred at 110° C. overnight. The solution was cooled and flash chromatographed (10% MeOH/EtOAc) to give 1-(4-(5-(5-(2,6-dimethylphenylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.051 g, 46% yield) as a tan solid. 1H NMR (CDCl3) δ 1.77-1.94 (m, 4H), 2.10 (s, 3H), 2.38 (s, 6H), 2.43 (s, 3H), 2.80 (t, 1H), 3.04 (t, 1H), 3.20 (t, 1H), 3.88 (s, 1H), 4.53 (d, 1H), 6.53 (s, 1H), 7.13-7.23 (m, 5H), 7.64 (s, 1H), 8.42 (s, 1H), 9.02 (bs, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2cc(Nc3ccnc4[nH]c5c(c34)CNCC5)ccc2c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5ccccc5c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
Naphthalen-2-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (79 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (104 μL, 0.75 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 60 (24 mg, 26% yield) as a tan powder. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl.[Cl-].[Na+]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (11.0 g, 6.40 mmol) was dissolved in methanol (10 mL), sodium borohydride (242 mg, 6.40 mmol) was slowly added, and stirred at room temperature for 5 minutes. The mixture was cooled on an ice bath, 10% hydrochloric acid aqueous solution and sodium chloride were added, and the mixture extracted with ethyl acetate. The organic phase was washed with saturated brine, and dried by anhydrous sodium sulfate. The sodium sulfate was filtered off, and the product concentrated under reduced pressure to obtain the target compound (614 mg, 61%) as a light yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Temperature: 60 °C

Procedure:
A mixture of 21.15 g (0.08 mole) of 4-(6-hydroxyhexyloxy)cinnamic acid (13), 11.63 g (0.096 mole) of N,N-dimethylaniline 8.69 g (0.096 mole) of acryloyl chloride, 0.05 g of 2,6-di-t-butyl-4-methylphenol and 60 ml of 1,4-dioxane was heated at 60° C. under a nitrogen atmosphere. After 2 hours heating at 60° C. the mixture was filtered and dropped under stirring into a mixture of 1000 ml of water, 400 g of ice and 10 ml of 2.4 N hydrochloric acid. The solid precipitate was filtered off and recrystallized from 350 ml of ethanol. The solid was dried in a desiccator over silica gel. Yield 19.7 g (77.3%).
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CC#N.C1COCC1>[CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[N:16]([CH3:29])[C:15]1=[O:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccccc2)cn(C(c2ccccc2)c2ccccc2)c1=O
Yield: 43 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 16 (Step 1) starting from 1-benzhydryl-5-phenyl-pyrimidine-2,4-dione (prepared as in Example 14, Step 2) (0.37 g, 1.01 mmol); a 1:1 mixture of was dry MeCN/THF and iodomethane were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.16 g, 43%) as a light-red solid. 1H NMR (400 MHz, CDCl3): δ 3.46 (s, 3H), 7.19-7.24 (m, 6H), 7.28-7.43 (m, 11H). MS (ESI) m/z: 369 [m-H]+.
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)#[CH:2].C([Mg]Br)C.[CH2:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]=[C:3]([C:1]#[C:2][CH2:23][OH:24])[C:9]=2[CH:10]=1
Reactant: C=O
Reactant: C#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
A solution of 13.5 g. of 10-ethynyl-8-chloro-dibenzo[b,f]thiepin in 150 ml. of absolute tetrahydrofuran is treated dropwise at room temperature with 52 ml. of a 1-M solution of ethylmagnesium bromide solution in tetrahydrofuran. After stirring the mixture for an additional hour, 1.85 g. of paraformaldehyde are pyrrolyzed and led through the mixture in gaseous form. The solution, having now warmed to about 50° C., is stirred for an additional 30 minutes and then poured onto a saturated, aqueous ammonium chloride solution. By extraction with benzene and subsequent chromatography on silica gel using benzene/methanol (20:1) as the eluant, there is obtained 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol which melts at 111°-113° C. after recrystallization from ethyl acetate/petroleum ether.