Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][CH:5]=[N:6][C:7]=1[C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1.P(Cl)(Cl)([Cl:32])=O>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:7]2[C:2]([F:1])=[C:3]([Cl:32])[N:4]=[CH:5][N:6]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1nc[nH]c(=O)c1F)n2Cc1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncnc(Cl)c1F)n2Cc1ccc(F)cc1

Procedure:
A mixture of 5-fluoro-6-(1-(4-fluorobenzyl)-5 methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3H-pyrimidin-4-one obtained in Example 36 (4) (20 mg) and phosphorus oxychloride (1 ml) was heated, under reflux for 3 hours. The mixture was concentrated under reduced pressure, diluted with dichloromethane, washed with water, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=1:99) to obtain the desired product (13 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[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:22])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([Cl:22])=[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)cccc1Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(F)cccc1Cl
Temperature: 100 °C

Procedure:
A stirred suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide (11.4 g, 0.04 mol) in thionyl chloride (100 mL) was heated at 100° C. for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The resulting residue was azeotroped with toluene (100 mL). The crude residue was triturated with diethyl ether to afford the title compound as an off-white solid (12.1 g, quantitative). LCMS (Method E): RT=3.88 min, m/z: 305 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: Oc1c(Cl)c(F)cc(F)c1Cl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Reaction time: 2 h

Procedure:
20 g of 2,6-dichloro-3,5-difluorophenol are initially introduced in 70 ml of acetic acid, and 8 g of 98% strength nitric acid are added dropwise. Stirring is subsequently continued at room temperature for 2 hours, and the mixture is taken up in 150 ml of dichloromethane and washed twice with water. After the dichloromethane has been distilled off, 18 g of product remain. Purity 94% according to GC analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Cc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 24.1 %

Procedure:
A solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was treated with α-toluenesulfonyl chloride (38 mg, 0.2 mmol), heated in a microwave reactor at 120° C. for 120 minutes, cooled to 25C and concentrated under reduced pressure. The residue was triturated with water (1 ml), filtered, and washed with hexane:ethyl acetate (1:1). The crude product was chromatographed on silica gel, eluting with dichloromethane:methanol (399:1) to give the title compound (7 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.62 Hz, 6 H) 1.58 (m, 2 H) 1.69 (m, 1 H) 4.49 (m, 2 H) 4.59 (s, 2 H) 7.32 (m, 5 H) 7.51 (m, 2 H) 7.57 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.38 (s, 1 H) 14.08 (s, 1 H) 15.14 (s, 1 H) (ESI−) m/z 580 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O[Li].O>CO.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COC(=O)C1(c2ccc3onc(C)c3c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1noc2ccc(C3(C(=O)O)CC3)cc12
Yield: 32.2 %

Procedure:
To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (0.80 g, 19 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature overnight before the MeOH was removed by evaporation under vacuum. Water and Et2O were added and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 1H NMR (400 MHz, DMSO) δ 12.40 (br s, 1H), 7.76 (s, 1H), 7.60-7.57 (m, 2H), 2.63 (s, 3H), 1.52-1.48 (m, 2H), 1.23-1.19 (m, 2H). MS (ESI) m/z (M+H+) 218.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13](O)(=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C>ClCCl>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCl (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with 1 N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C28H39NO4=453.61; found: [M+H]+=454.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-methylhydrazinecarboxylic acid tert-butyl ester (0.62 g, 4.20 mmol) in methylene chloride (10 ml) was added acetic acid anhydride (0.79 ml, 8.40) and pyridine (1.36 ml, 16.80 mmol) and the mixture was stirred overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g (41%) of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:41][CH2:40][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([O:34]C)=[O:33])[C:18]3=[O:39])[CH2:16][CH2:15]2)[C:3]1=[O:42].[OH-].[Li+].CO>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([OH:34])=[O:33])[C:18]3=[O:39])[CH2:40][CH2:41]2)[C:3]1=[O:42]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C)c5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(=O)n(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccccc2)c2ccccc21
Temperature: 35 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
A solution of methyl 3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (326 mg, 0.575 mmol, 1 equiv) and lithium hydroxide (48.3 mg, 1.15 mmol, 2.0 equiv) in a 4:1 mixture of methanol and water (5 ml t/v) was stirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (56 mg, 17%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=6.8 Hz); 2.37 (t, 2H, J=7.2 Hz, J=6.4 Hz); 2.54-2.59 (m, 2H); 2.66-2.73 (m, 4H); 3.32 (s, 3H); 3.91 (t, 2H, J=6.8 Hz); 4.58 (s, 2H); 4.60 (s, 2H); 6.76 (t, 1H, J=7.2 Hz); 6.85 (d, 2H, J=8 Hz); 7-7.07 (m, 2H); 7.12-7.15 (m, 1H); 7.2-7.26 (m, 3H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 12.9 (bs, 1H); MS for C32H35N5O4 m/z 554.05 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[NH:18][C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[CH2:36]O>C1COCC1>[F:24][C:4]([F:3])([F:23])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:20][C:19](=[O:21])[N:18]([CH2:36][C:27]3[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=3[I:25])[C@@H:17]([CH3:22])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: OCc1cc(C(F)(F)F)ccc1I
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil; 5.6 mg; 0.139 mmol) in THF (0.5 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 22; 50 mg; 0.153 mmol) in THF (1 mL) dropwise. The resultant mixture stirred at 0° C. for 15 min prior to dropwise addition of 2-(bromomethyl)-1-iodo-4-trifluoromethyl)benzene (Intermediate 11; 50.7 mg; 0.139 mmol) as a solution in THF (0.5 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and partitioned between EtOAc (25 mL) and H2O (15 mL). The aqueous layer was re-extracted with EtOAc (3×25 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=611.7 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.91 (s, 2H), 7.89 (s, 1H), 7.52 (s, 1H), 7.29-7.26 (m, 1H), 5.44 (d, J=10.8 Hz, 1H), 4.88 (d, J=16.5 Hz, 1H), 4.62 (d, J=16.5 Hz, 1H), 3.77-3.70 (m, 1H), 2.45 (dd, J=14.1, 5.4 Hz, 1H), 2.06-1.98 (m, 1H), 1.22 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:6][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:4]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:29])[F:28])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC(C)=O
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), acetone (37 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) was added sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then filtered, concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 6.8%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.2.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][N:15]=[C:16]=[O:17]>O1CCCC1>[CH3:14][NH:15][C:16](=[O:17])[NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) and methyl isocyanate (1 ml.) were stirred in tetrahydrofuran for 2 hours at room temperature. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from ethanol to give yellow prisms of 5-methylureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.06 g.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCCCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 123.5 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9H-purine-2,6-diamine (250 mg) in dry N,N-dimethylformamide (4.46 ml) at room temperature was added potassium carbonate (395 mg). The reaction mixture was stirred at 60° C. for 90 min. The reaction was cooled to room temperature and 4-(tetrahydro-2H-pyran-3-yl)butyl methanesulfonate (186 mg) was added and the reaction stirred at 90° C. for 2 hours. The reaction mixture was taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil (366 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (30-70%) to afford the title compound as an orange gum (172 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([N:1]2[C:5]3[N:6]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=3[CH:3]=[CH:2]2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2ccn(-c3ccc([N+](=O)[O-])cc3)c2n1
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (120 mg, 0.55 mmol) in DMF (3 mL) at rt, was added NaH (60% in mineral oil, 26.4 mg, 0.66 mmol). The mixture was stirred for 10 min and 4-fluoronitrobenzene (155 mg, 1.1 mmol) was added to the reaction. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with sat. aq. sodium citrate solution, extracted with EtOAc and dried over MgSO4. The product was purified by flash column chromatography (SiO2, 25% EtOAc/CH2Cl2) to give a yellow solid (137 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]([CH3:26])[C:4](=[O:25])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1,2-dihydroquinolin-2-one (370 mg, 0.86 mmol, 1.00 equip), potassium carbonate (355 mg, 2.57 mmol, 3.00 equip), and N,N-dimethylformamide (10 mL). To the resulting mixture was then added CH3I (182 mg, 1.28 mmol, 1.50 equip) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 447 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][C:8]([CH3:13])([CH:11]=[O:12])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14][Mg+].[Br-]>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH2:9][C:8]([CH:11]([OH:12])[CH3:14])([CH3:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C[Mg+]
Reactant: CC(C)CC1=CCC(C)(C=O)CC1
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C)(C(C)O)CC1
Yield: 89.9 %

Procedure:
4-Isobutyl-1-methylcyclohex-3-enecarbaldehyde 3a (20 g, 111 mmol) was dissolved in diethyl ether (120 ml) and the solution stirred under nitrogen. An ice-bath was used to keep the temperature below 20° C. while MeMgBr (3M, 48 ml, 144 mmol) was added over 30 min. The ice-bath was removed and the reaction stirred for a further 30 min before being poured slowly, and under nitrogen, onto 2M HCl (50 ml). The phases were separated and the upper organic phase washed twice with brine (2×100 ml), dried (MgSO4) and concentrated in vacuo to give 19.6 g of a colorless oil. The product was purified by distillation (0.1 mbar, 90° C.) to give 4c as a 4:5 mixture of diastereomers containing 6.5% of a third isomer (14 g, 52% yield, colourless oil, 95% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=O)[CH2:11]3)[CH2:9][N:8]([C:20](=[O:28])[NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:5]2=[CH:6][CH:7]=1.[CH3:29][NH2:30].O1CCCC1.N.CO>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:30][CH3:29])=[O:18])[CH2:11]3)[CH2:9][N:8]([C:20]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:28])[C:5]2=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 45, with the exceptions that the methyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate obtained in Example 58 was used instead of ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate, and that a solution of methylamine-tetrahydrofuran was used instead of a saturated solution of ammonia-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1[O:24][C:23]2[CH:22]=[CH:21][C:20]([OH:25])=[CH:19][C:18]=2[O:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][O:25][C:20]1[CH:21]=[CH:22][C:23]2[O:24][CH2:16][O:17][C:18]=2[CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: Oc1ccc2c(c1)OCO2
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Yield: 73.1 %

Procedure:
By the same procedure as in Example 26-B), while using (2S)1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)Pyrrolidine (2.00 g) and (3,4-methylenedioxy)phenol (2.72 g), there was obtained 2.41 g of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].P(S)(OCC)(OCC)=[S:29]>O.ClCCl>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:10](=[S:29])[NH2:11])=[CH:12][C:13]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=2)[N:19]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOP(=S)(S)OCC
Reactant: CCCc1c2nc(-c3cc(C#N)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Solvent: ClCCl
Solvent: O
Product: CCCc1c2nc(-c3cc(C(N)=S)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Temperature: 25 °C

Procedure:
Water (2 drops) was added to a stirred suspension of 6-isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)-nicotinonitrile (Example 36) (150 mg, 0.41 mmol) in (EtO)2P(S)SH (0.5 mL). The mixture was stirred at room temperature. After 5 h more (EtO)2P(S)SH (0.5 mL) was added and dichloromethane (5 mL) added to aid stirring. After 14 h the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After filtration and separation of the phases the organics were washed again with saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated. The product was purified by flash column chromatography (gradient elution from 100% dichloromethane to 96% dichloromethane:methanol) to give 80 mg product.