Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[S:12]1CC(O)S[CH2:14][CH:13]1O.C(NCC)C>C(O)C>[NH2:5][C:4]1[S:12][CH:13]=[CH:14][C:3]=1[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:1]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccccc1
Solvent: CCO
Solvent: CCNCC
Product: Nc1sccc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
Following a procedure described in J. Med. Chem. 2002, 45, 382-389; 1.45 g (10 mmol) 3-oxo-3-phenyl-propionitrile, 0.76 g (5.0 mmol) [1,4]dithiane-2,5-diol, 0.40 ml (10 mmol) diethylamine and 5 ml ethanol were charged in a sealed tube. The reaction mixture was heated at 50° C. for 6 h. The tube was then placed in a fridge (about 4° C.) for the night, and the product was collected by filtration and dried under vacuum to afford 0.42 g (23%) (2-amino-thiophen-3-yl)-phenyl-methanone as a light brown crystals. ES-MS m/e (%): 204 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C)n(-c2cccc(F)c2)c1-c1ccccc1

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids filtered away and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 100° C.-101° C.).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.C=[O:11].[NH2:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:28])[C:17]=2[C:16](Br)=[CH:15][C:14]=1[Br:30]>O>[NH2:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:28])[C:17]=2[C:16]([OH:11])=[CH:15][C:14]=1[Br:30]
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
Hydrolysis is carried out by adding 195.3 parts of 66% oleum and 16 parts of paraformaldehyde to the reaction mixture and heating it to 110° C. The mixture is heated in a stream of nitrogen to 110° C. until the presence of 1-amino-2,4-dibromoanthraquinone can no longer be detected. The reaction time is from 1 to 2 hours. Upon completion of the reaction, the reaction mixture is cooled to room temperature and diluted with 523 parts of water. The precipitated crystals of 1-amino-2-bromo-4-hydroxyanthraquinone are isolated by filtration and washed with water until neutral, affording 149 parts of product, corresponding to a yield of 93.7%, based on 1-aminoanthraquinone. Melting point: 226°-228° C. (lit.: 231°-232° C.). According to elemental analysis, the bromine content is 25.0% (calculated: 25.2%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N([C@@H]2C[C@H]2c2ccccc2)CC1(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN([C@@H]2C[C@H]2c2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 7.0 g (0.020 mole) of 2-chloro-7,7-difluoro-9-(trans-2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-287) in 140 mL of dimethylformamide was added 9.7 g (0.030 mole) of cesium carbonate, followed by 3.7 mL (0.060 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of 2-chloro-7,7-difluoro-5-methyl-9-(trans-2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-287) as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[NH:33][CH:30]1[CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(Cc4ccccc4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18ClN5O2, 419.9
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1.F[B-](F)(F)F.[H+].[CH3:40][Si](C=[N+]=[N-])(C)C.CCCCCC.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:40][O:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(-c2cccc([C@]34C[C@H](OC)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a 0° C. mixture of N-((4aR,6R,7aS)-6-hydroxy-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.086 g, 0.169 mmol) and 48% aqueous fluoroboric acid (0.031 g, 0.169 mmol) in dichloromethane (0.6 mL) is added 2 M trimethylsilyldiazomethane in hexane (0.101 mL, 0.202 mmol). The mixture is stirred at 0° C. for 30 minutes and is poured into saturated aqueous solution of sodium bicarbonate. The mixture is diluted with water and is extracted with dichloromethane. The organic layer is washed sequentially with water and brine and is dried over sodium sulfate. The solvent is removed under reduced pressure and the crude product is purified by silica gel chromatography eluting with a linear gradient of 10% to 60% ethyl acetate in hexanes over 20 minutes to give the title compound (0.038 g, 48%). ES/MS m/e: 473 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:11][C:7]4[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][CH:8]=4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C(O)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)n1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H17ClN2O3: 404, observed (M+H)+: 405.2 1H NMR (400 MHz, DMSO-d6) δppm 2.12 (dd, J=9.09, 4.80 Hz, 1 H) 2.39 (dd, J=8.08, 4.80 Hz, 1 H) 3.22 (t, J=8.59 Hz, 1 H) 5.14 (s, 2 H) 6.15 (d, J=7.33 Hz, 1 H) 6.73 (t, J=7.45 Hz, 1 H) 6.88 (d, J=7.58 Hz, 1 H) 7.00-7.10 (m, 1 H) 7.26 (d, J=1.01 Hz, 1 H) 7.38 (s, 4 H) 7.84-7.98 (m, 2 H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:13][O:14][C:15](=[O:37])[C:16]1[CH:21]=[C:20](Br)[CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25]>>[CH3:13][O:14][C:15](=[O:37])[C:16]1[CH:21]=[C:20]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:25]
Reactant: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: C#CCCCCCCCCCC
Product: CCCCCCCCCCC#Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 73 %

Procedure:
Following the procedure of Example 351, using 1-dodecyne instead of ethynyl biphenyl, 1.0 g (2.336 mmol) of the product of Example 202 gives 0.874 g (73%) of the alkyne as a brown oil. Electrospray Mass Spec: 514.4 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1.CS(C)=O.CCOC(C)=O>O>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CC#N)cn1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
Sodium cyanide (38.6 g, 787.7 mmol, 1.5 equiv), 5-(chloromethyl)-2-methylpyridine (74.37 g, 527.4 mmol, 1 equiv) and DMSO (750 mL, 10 vol) were charged into a reactor and placed under nitrogen. This exothermic mixture self-heated to ca. 45° C. and was heated to 60° C. After 15 min, TLC (eluent: EtOAc:heptanes 50/50) indicated that the reaction was completed. The mixture was cooled to RT and water (1500 mL, 20 vol) was added slowly; the exotherm was controlled by the addition rate. The solution was extracted with EtOAc (4×750 mL), and the combined organic layer was concentrated under reduced pressure. The resulting oil was purified by chromatography (eluent: EtOAc), to obtain 2-(6-methylpyridin-3-yl)acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][C@@H:30]([CH2:34][OH:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][C@@H:30]([CH2:34][OH:35])[CH2:29]2)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: OC[C@H]1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 51.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (R)-morpholin-2-ylmethanol hydrochloride (0.24 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.41 g, 51%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:38])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:80]1[CH:84]=[CH:83][CH:82]=[C:81]1[C:85](O)=[O:86]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:38])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:12][NH:13][C:85]([C:81]1[S:80][CH:84]=[CH:83][CH:82]=1)=[O:86]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
To a solution of (S)-3-Amino-2-({5-[(1H-indazol-4-ylmethyl)-carbamoyl]-3-isopropyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester trifluoro-acetic acid salt (0.33 mmol) in anhydrous DMF (8 mL) was added triethylamine (0.14 mL, 0.57 mmol), HBTU (0.188 g, 0.50 mmol), HOBt (0.054 g, 0.40 mmol), and 2-Thiophenecarboxylic acid (0.051 g, 0.40 mmol). The mixture was stirred at room temperature 15 h, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-100% EtOAc in hexane) to give 0.1096 g (60%) white foam. MS m/e 554.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35 g, 2.22 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.59 g, 73%). MS (ISP) 404.0 [(M+H)+]; mp 147° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][NH:29][CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][F:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][N:29]([CH2:34][CH2:35][F:36])[CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCNC3)C2)c(F)c1
Reactant: FCCBr
Product: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCN(CCF)C3)C2)c(F)c1

Procedure:
According to Method X, 6-cyclopropylmethoxy-2-[4-(2,7-diaza-spiro[4.4]non-2-yl)-3-fluorophenyl]-2H-isoquinolin-1-one was reacted with 1-bromo-2-fluoro-ethane. In this way the product was obtained with molecular weight 479.57 (C28H31F2N3O2); MS (ESI): 480 (M+H+).
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[N:11]=[C:10]([CH2:12]O)[C:9]([F:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[N:11]=[C:10]([CH2:12][Br:3])[C:9]([F:14])=[CH:8][CH:7]=1
Reactant: OCc1nc(Br)ccc1F
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1ccc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a stirred solution thionyl bromide (2.44 g, 11.78 mmol, 1.05 eq.) in 50 ml dry DCM, cooled to 5° C., was added dropwise a solution of (6-bromo-3-fluoropyridin-2-yl)methanol (2.54 g, 11.22 mmol, 1 eq.) and pyridine (0.931 g, 11.78 mmol, 1.05 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 150 ml of water and 150 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried of MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 6-bromo-2-(bromomethyl)-3-fluoropyridine (2.89 g, 87% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][CH2:13][CH3:14])[N:6]=[CH:7]2.[I-].CS[C:18]1[S:19][CH2:20][C@@H:21]2[CH2:30][C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][N+:22]=12>>[CH2:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:18]1[N:22]3[CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH2:30][C@H:21]3[CH2:20][S:19]1)[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH3:14]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CCCc1cc2c(N)cccc2cn1
Agent: [I-]
Product: CCCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Yield: 97.3 %

Procedure:
By following the procedure of Example 3 but using 5-amino-3-propylisoquinoline (0.18 g) and (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (0.35 g) as starting materials, (S)-3-[(3-propylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (0.35 g) is obtained in a crude form, which is purified by chromatography on a column (diameter of the column: 0.7 cm) containing silica (6 g) by eluting with methylene chloride and collecting the eluate in 20 cc fractions.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[NH2:28][C:29]1[N:33](C(OC(C)(C)C)=O)[N:32]=[C:31]([CH2:41][CH2:42][C:43]2[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[CH:44]=2)[CH:30]=1.[NH4+].[Cl-]>C1COCC1>[CH3:50][O:49][C:47]1[CH:48]=[C:43]([CH2:42][CH2:41][C:31]2[NH:32][N:33]=[C:29]([NH:28][C:22](=[O:24])[C:21]3[CH:20]=[CH:19][C:18]([CH:15]4[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]4)=[CH:27][CH:26]=3)[CH:30]=2)[CH:44]=[C:45]([O:51][CH3:52])[CH:46]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(C4CCN(C)CC4)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
A solution of NaHMDS (1M in THF) (5.91 mL, 5.91 mmol) was added dropwise to a stirred solution of methyl 4-(1-methylpiperidin-4-yl)benzoate (0.4594 g, 1.97 mmol) and tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.821 g, 2.36 mmol) in THF (4 mL), over a period of 10 mins under nitrogen. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was poured into saturated NH4Cl (25 mL), extracted with EtOAc (2×25 mL), washed with saturated brine and dried over MgSO4, filtered and evaporated to afford the crude product (1.0719 g) as an orange gum. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.142 g, 16.08%) as a white solid;
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15]=[C:16]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][C:8]=1[C:27]([F:30])([F:29])[F:28])C>[OH-].[Na+].C(O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:16]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)=[CH:15][CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[C:8]([C:27]([F:30])([F:28])[F:29])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(SCC=C(c2ccco2)c2ccco2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(SCC=C(c2ccco2)c2ccco2)cc1C(F)(F)F

Procedure:
A solution of {4-[3,3-bis-(2-furanyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester (35 mg, 0.077 mmol) in 1N NaOH (0.1 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours. The reaxtion mixture was evaporated and the residue dissolved in 1 N HCl (0.15 ml). The aquous phase was extracted with methylene choride (3×25 ml), dried (MgSO4) and evaporated to give the title compound in 30 mg (92%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.Br[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31]([C:44]3[CH:45]=[N:46][CH:47]=[N:48][CH:49]=3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cncnc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]-pyrimidin-4-one (prepared as described in example 51, 0.500 g, 0.829 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 5-bromopyrimidine (0.200 g, 1.24 mmol), cesium carbonate (0.540 g, 1.66 mmol), Pd(dppf)2Cl2 (0.060 g, 0.082 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 2 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography over silica gel (60-120 mesh) to afford 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-(4-pyrimidin-5-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ 9.18 (s, 1H), 9.15 (m, 2H), 8.67 (m, 1H), 8.61 (m, 1H), 8.55 (m, 1H), 7.96 (m, 1H), 7.90 (m, 1H), 7.82 (m, 2H), 7.61 (m, 2H), 7.46 (m, 4H), 3.30 (s, 3H); LC-MS calculated for C28H19ClN6O3S (M+H+) 555.1, found 554.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([NH2:24])=[C:22](I)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:26]([OH:31])[CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:24][C:23]1[C:22]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][OH:31])=[N:21][CH:20]=[N:19][C:18]=1[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1c(I)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C#CCCCO)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
To a solution of N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4,5-diamine (300 mg) and 4-pentyn-1-ol (65 mg) in acetonitrile-triethylamine (6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 24 hrs. 4-Pentyn-1-ol (65 mg), bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(I) iodide (7.3 mg) were added to the reaction system and the mixture was stirred at 60° C. for 2 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=1:19) to give the title compound (157.2 mg) as a yellow solid.