Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[C:32]([CH:33]=O)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:32]3[C:23](=[O:22])[NH:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1CNC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (65 mg, 0.448 mmol) and 3 Å molecular sieves (100 mg) in methanol (6.0 mL) was heated at reflux for 2.5 hours under nitrogen atmosphere. It was cooled to 0° C. and sodium triacetoxy borohydride (189.5 mg, 0.996 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and purified through silica gel plug (eluting with 15% methanol in methylene chloride) to give title compound (71 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:15])[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[N:6]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:15])[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9])[N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)COC(=O)C(=O)c1csc(N)n1
Solvent: C1CCOC1
Product: CC(C)COC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 1 g of isobutyl 2-aminothiazol-4-ylglyoxylate, 620 mg of phenyl isocyanate and 10 ml of tetrahydrofuran. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.[C:16]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reaction time: 1.25 h
Yield: 100 %

Procedure:
916 mg (5 mmol) of 2-hydroxy-4-nitro-benzoic acid is dissolved in a mixture that consists of 8 ml of methanol and 32 ml of toluene, and it is slowly mixed with a solution of trimethylsilyldiazomethane in hexane (2 molar). After the addition is completed, stirring is continued for 1.25 hours at room temperature. After the reaction mixture is concentrated by evaporation, 1 g (about 100% of theory) of 2-hydroxy-4-nitro-benzoic acid methyl ester is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:32][CH:31]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: O=C(O)Cc1cccc(I)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(C(=O)NNC(=O)Cc2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Add 1,1-carbonyldimidazole (0.72 g, 4.40 mmol) to a solution of 3-iodo-phenylacetic acid (1.20 g, 4.6 mmol) in 40 mL of N,N-dimethylacetamide, followed by N,N-diisopropylethylamine (0.79 mL, 4.40 mmol). Stir the mixture at room temperature for 2 h, add 4-cyano-benzoic acid hydrazide (0.64 g (4.0 mmol) and heat the mixture to 60° C. for 2 h. Cool the mixture to room temperature and dilute with H2O causing a solid to precipitate from solution. Collect the precipitate by filtration, wash with H2O and diethyl ether dry. Collect any further material that may crystallize from the filtrate. Extract the filtrate with CH2Cl2 and concentrate the combined organic phase provide a clear liquid. Dilute this mixture with H2O resulting in a third crop of material to precipitate from solution. Collect and combine all solid material to give 1.31 g, 71% yield of 4-cyano-benzoic acid N′-[2-(3-iodo-phenyl)-acetyl]-hydrazide as a powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17].[OH-].[Na+].Br[CH2:33][C:34]([OH:36])=[O:35].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:33][C:34]([OH:36])=[O:35])[CH2:21][CH2:20]1)=[O:17]
Reactant: COc1ccc(C(=O)NC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)NC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 360 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride and 162 mg NaOH in 20 ml EtOH/H2O 1:1 142 mg bromo acetic acid was added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: I[C:2]1[C:3](=[O:21])[NH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Zn].C(O)(=O)C>[O:8]([C:7]1[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:4][C:3](=[O:21])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc(Oc2ccccc2)c1I
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1cc(Oc2ccccc2)nc(-c2ccccc2)[nH]1
Yield: 125.6 %

Procedure:
A mixture of 7.07 g (18.1 mmol) of crude 5-iodo-6-phenoxy-2-phenyl-4(3H)-pyrimidinone, 2.02 g (31.1 mmol) of zinc dust and 25 mL of glacial acetic acid was heated to reflux. After 15 min an additional 2.06 g (31.7 mmol) of zinc dust was added, followed 15 min later by a further 2.04 g (31.4 mmol) of zinc dust. The mixture was maintained at reflux for 2 h, cooled and filtered to remove unreacted zinc. The filtrate was rotovaped to leave a semi-solid which was triturated with 75 mL of boiling water to afford 6.01 g (57% from 4,6-dihydroxy-2-phenylpyrimidine) of 6-phenoxy-2-phenyl-4(3H)-pyrimidinone as a yellow solid. 1H-NMR (d6-DMSO)δ5.5 (1H,s), 7.1-7.5 (8H), 8.1 (2H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]([NH2:46])=[O:45])[CH:42]=3)[N:37]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:36]=2)[CH:32]=[CH:33][CH:34]=1>ClCCl.CN(C)C=O>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:28][C:29]1[CH:30]=[C:31]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]([NH2:46])=[O:45])[CH:42]=3)[N:37]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:36]=2)[CH:32]=[CH:33][CH:34]=1)=[O:6]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1

Procedure:
To a solution of 2-(dimethylamino)acetic acid hydrochloride (0.091 g, 0.649 mmol) in 6 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (EDCI) (0.135 g, 0.708 mmol) and triethyl amine (0.090 mL, 0.649 mmol). The reaction was stirred at room temperature for 10 min before 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) dissolved in 1 mL of dichloromethane, was added to the solution. Dimethyl formamide (2 mL) was added to aid solubility. Additional reagent (1 equivalent) was necessary to drive the reaction to completion. The reaction mixture was then partitioned between water and dichloroethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 422 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH2:14])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH:14][CH:2]([CH3:4])[CH3:1])=[CH:8][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)c[nH]c4c3)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC[C@H](c1ccc(Cl)cc1)c1c[nH]c2cc(-c3ncnc4c3[C@H](C)CC4)ccc12
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Acetone (0.0195 mL, 0.266 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanamine (107 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.139 mL, 0.797 mmol) in methylene chloride (2.0 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (0.0188 g, 0.0885 mmol) was added. After stirring for 2.5 hours, saturated NaHCO3 was added, and the mixture was stirred vigorously 10 minutes. The mixture was extracted with DCM (3×10 mL). The combined organic were dried (Na2SO4), filtered and concentrated. The crude product was purified by SFC chiral chromatography (Chiral OJH (21.2×250 mm) 25% methanol+0.1% TEA) to give N—((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine (19.8 mg, 16.8%) as the first peak. LCMS: M+1 445.3. 1H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.49-7.46 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.36 (t, 1H), 3.89 (m, 1H), 3.23 (m, 1H), 3.14-2.99 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (m, 1H), 2.34 (m, 1H), 1.68 (m, 1H), 0.96 (d, 6H), 0.92 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9]C)=[CH:4][CH:3]=1.[C:12]([O-])(O)=[O:13].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:11]=[C:12]=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC[C@H](N)c1ccc(Br)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N=C=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)propan-1-amine (5 g, 25 mmol) in CH2Cl2 (10 mL) was added saturated aqueous NaHCO3 (10 mL) and then triphosgene (2.45 g, 8 mmol) at 0. Then the reaction mixture was stirred for 15 minutes at 0° C. under nitrogen. The reaction mixture was extracted with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford (R)-1-bromo-4-(1-isocyanatoethyl)benzene (2.5 g, 44%), which was used for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][N:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([C:37]1[CH:41]=[CH:42][C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[O:14][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:22][C:21]3=[O:23])=[N:35][CH:36]=1)(=[O:39])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3ccc(C(N)=O)cn3)ccc1O2
Temperature: 100 °C

Procedure:
1′-tert-butoxycarbonyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one (40.0 g, 90.0 mmol), 6-chloronicotinamide (17.0 g, 108 mmol), Pd(PPh3)4 (5.21 g, 4.51 mmol), and aqueous 2M Na2CO3 (100 ml) solution were suspended in dioxane (300 ml) and heated at 100° C. for 16 h. The reaction mixture was diluted with CHCl3 and H2O, the aqueous layer was extracted with CHCl3. The combined organic layer was washed with brine, dried over MgSO4 and silicagel. The desiccant was removed through celite filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by crystallization (CHCl3-EtOAc) to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([S:12]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][N:15]=3)=[O:32])=[N:11][C:6]2=[CH:5][C:4]=1[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc(C)c(OC)nc3[nH]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccnc(CS(=O)c2nc3cc(C)c(OC)nc3[nH]2)c1C
Temperature: -30 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine (784 mg, 2.37 mmol) was dissolved in a mixture of methanol (6 ml) and toluene (54 ml). Metachloroperbenzoic acid (566 mg) in a mixture solution of methanol (3 ml) and toluene (3 ml) were added thereto at −40° C. under nitrogen flow, and the reaction mixture was stirred at −20 to −40° C. for 2 hours. After the reaction was completed, a sodium bicarbonate solution was added, and the organic layer was separated. The aqueous layer was extracted with chloroform (40 ml), combined with the organic layer and dried over sodium sulfate, the solvent was evaporated and the residue was obtained which was then precipitated as a solid from a mixture of chloroform and ether, thereby yielding the title compound (654 mg, 1.89 mmol, 80%) as a purple gray solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:21]C1C=CC=CC=1)[NH:5][C@@H:6]1[C:11]2[CH:12]=C(C#N)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].N[C@@H:29]1[C:34]2C=N[CH:37]=[CH:38][C:33]=2OC(C)(C)[C@H:30]1O.Cl.C[N:44](C)CCCCCN=C=N>CN(C)C=O>[C:1]([N:3]=[C:4]([NH2:21])[N:5]([C:30]1[CH:29]=[CH:34][CH:33]=[CH:38][CH:37]=1)[C@@H:6]1[C:11]2[CH:12]=[N:44][CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:18])([CH3:19])[C@H:7]1[OH:20])#[N:2]
Reactant: CC1(C)Oc2ccncc2[C@@H](N)[C@@H]1O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Reactant: CN(C)CCCCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccncc2[C@@H](N(C(N)=NC#N)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
To a solution of the title A compound from Example 3 (2.2 g, 12.5 mmol) and (trans)-4-amino-3,4-dihydro-2,2-dimethyl-2H-pyrano[3,2-c]pyridin-3-ol (1.1 g, 5.7 mmol) (prepared according to EP 0 205 292 A2) in dimethylformamide (5 ml) under argon, 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (2.2 g, 10.8 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between water (pH ~11) and ethyl acetate. The organic phase was separated and the aqueous phase was reextracted with ethyl acetate and the combined organic phase was washed with water, aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (acetone:dichloromethane/1:4) to yield a colorless solid (470 mg) which was crystallized from acetonitrile to provide the title compound, m.p. 233°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9](Cl)=[O:10].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:10]
Reactant: c1c[nH]cn1
Reactant: CCCN(C(=O)Cl)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(C(=O)n1ccnc1)c1ccccc1Cl

Procedure:
of N-2-chlorophenyl-N-propylcarbamoyl chloride, 14g. off imidazole and 30 ml. triethylamine were refluxed in 200 ml. of dry tetrahydrofuran for 5 hours. The reaction mixture was poured into 2 liters of water and the slurry chilled causing some separation from the aqueous phase. A slightly sticky crystalline solid was collected, washed with water and dried in vacuo. It was recrystallised from a mixture of toluene and light petroleum (62°-68° C. fraction) with charcoaling. On cooling, an oil separated which soon solidified to give the product, 1-(N-2-chlorophenyl-N-propylcarbamoyl)imidazole m.p. 75.5°-76.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:18]([CH3:20])=[CH:17][C:16](=[O:21])[NH:15][C:14]=3[N:13]([CH3:22])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:22])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC)cc(-c2nn(C)c3[nH]c(=O)cc(C)c23)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c2c(-c3cc(OC)cc(OC)c3)nn(C)c2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 3-(3,5-dimethoxyphenyl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.0 g, 3.34 mmol) in DMF (5 ml) were added DIPEA (1.17 ml, 6.68 mmol) and ethyl 2-bromoacetate (0.56 ml, 5.01 mmol). After stirring at 90° C. for 1 h the mixture was cooled to rt, water was added and extracted three times with CH2Cl2. The organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (eluent 50% hexane in EtOAc) to yield 910 mg (71%) of the title compound. [1H-NMR (DMSO-d6, 600 MHz): δ 6.71 (d, 2H), 6.61 (s, 1H), 6.57 (br s, 1H), 4.98 (s, 2H), 4.18 (q, 2H), 3.91 (s, 3H), 3.78 (s, 6H), 2.37 (s, 3H), 1.21 (t, 3H); UPLC-MS RtJ=1.21 min; [M+H]+=386.1]
Reaction SMILES: [CH2:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH2:8][OH:9])=[C:6]([F:14])[C:5]=1[F:15])[C:2]#[CH:3].[Cl-:16].[Li+].[ClH:18]>C(#N)C>[Cl:16]/[C:2](=[CH:3]\[Cl:18])/[CH2:1][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([CH2:8][OH:9])=[C:10]([F:13])[C:11]=1[F:12]
Reactant: C#CCc1c(F)c(F)c(CO)c(F)c1F
Reactant: [Cl-]
Reactant: Cl
Agent: [Li+]
Solvent: CC#N
Product: OCc1c(F)c(F)c(C/C(Cl)=C/Cl)c(F)c1F

Procedure:
A solution of 4-(prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.1 g) copper (II) chloride (1.3 g), and lithium chloride (0.62 g) in dry acetonitrile (23 cm3) was heated at the reflux temperature for 40 hours. The resulting dark solution was poured into dilute hydrochloric acid, and extracted into ethyl acetate. The organic phase was washed with more dilute hydrochloride acid, dried, and the solvent evaporated under reduced pressure to give Z-4-(2,3-dichloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol (0.1 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:36]1(C)[C:41]([SH:42])=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:44]([O-])([O-])=O.[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([S:42][C:41]3[CH:36]=[CH:37][C:38]([CH3:44])=[CH:39][CH:40]=3)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1S
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Sc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.0802 g, 0.15 mmol) in EtOH (1.5 mL) was added thiocresol (0.019 g, 0.15 mmol) and K2CO3 (0.0203 g, 0.15 mmol). The suspension was heated to 50° C. with stirring for 2.5 hours. The mixture was poured into H2O with constant stirring. The resulting precipitate was filtered, rinsed with H2O and dried to provide the desired product (yield: 0.060 g, 83%). mp 178-178° C. 1H NMR (300 MHz, DMSO d6) δ 2.19 (s, 3H), 3.23 (s, 3H), 6.95 (m, 2H), 7.08 (m, 2H), 7.52-7.66 (m, 3H), 7.72 (m, 1H), 7.88 (m, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 483 (M+H)+, 500 (M+NH4)+. Anal. calc. for: C24H19ClN2O3S2.0.75H2O: C, 58.05; H, 4.16; N, 5.64. Found: C, 57.99; H, 3.69; N, 5.76.
Reaction SMILES: C(OP([CH2:9][C:10]([O-:12])=[O:11])(OCC)=O)C.[H-].[Na+].O[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[C:18](=[O:29])[N:17]1[CH2:30][C:31]([F:34])([F:33])[F:32].C(=O)([O-])O.[Na+].[CH2:40]([CH2:43]OC)OC>>[O:29]=[C:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:16]([CH2:9][C:10]([O:12][CH2:40][CH3:43])=[O:11])[N:17]1[CH2:30][C:31]([F:34])([F:33])[F:32]
Reactant: CCOP(=O)(CC(=O)[O-])OCC
Reactant: COCCOC
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1CC(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Under argon, ethyl. (diethoxyphosphoryl)acetate (135 mg, 0.6 mmol) was dissolved in anhydrous dimethoxyethane (10 ml). 17.6 mg of NaH (60% in oil) were added at RT to this solution which was stirred at RT for 10 min. Afterward, a solution of 120 mg (0.04 mmol) of (RS)-3-hydroxy-2-(2,2,2-trifluoroethyl)-5-trifluoromethyl-2,3-dihydroisoindol-1-one in anhydrous dimethoxyethane (5 ml) was added and the mixture was subsequently stirred at reflux for 2 h. The reaction solution was left to cool; the reaction solution was then poured onto 50 ml of 5% sodium hydrogencarbonate solution and extracted twice with 20 ml each time of ethyl acetate; the organic phase was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel using DIP as the eluent. 90 mg (61%) of ethyl (RS)-[3-oxo-2-(2,2,2-trifluoroethyl)-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl]acetate were obtained as a colorless oil which crystallized from heptane as a beige solid.