Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH3:9])#[CH:2].[O:10](C)[S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12].[CH3:19]COCC>C(Cl)Cl>[F:15][C:14]([F:17])([F:16])[S:11]([O-:13])(=[O:12])=[O:10].[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([CH3:19])=[CH:5][C:4]=1[CH3:9])#[CH:2]
Reactant: CCOCC
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: C#Cc1ccncc1C
Solvent: ClCCl
Product: C#Cc1cc[n+](C)cc1C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Prepared according to Rubinsztajn et al. Tetrahedron Lett. 1992, 33, 14, 1821-1824. To a solution of 4-ethynyl-3-methylpyridine (420 mg, 3.58 mmol) in DCM (10 mL) at 0° C. was added methyl triflate (450 μL, 3.94 mmol), drop-wise. After stirring for 30 min at 0° C., ether was added and the precipitate was collected and dried, affording the title compound (863 mg, 86%) as a light brown solid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4](OCC)=O)[CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](C=O)[CH:13]=1.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>>[C:2]([C:3]1[CH:4]([C:3]2[CH:2]=[N:1][CH:11]=[CH:10][CH:9]=2)[C:25]2[C:21](=[N:22][NH:23][CH:24]=2)[NH:20][C:4]=1[CH:15]1[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]1)#[N:1]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=Cc1cccnc1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccnc1

Procedure:
The title compound was prepared from ethyl nipecotate, pyridine-3-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:3]([C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][CH:14]2[CH2:16][CH2:15]2)[CH:6]=1)=[O:4]
Reactant: Nc1nccs1
Reactant: COC(=O)c1c[nH]c2cnccc12
Reactant: BrCC1CC1
Product: O=C(Nc1nccs1)c1cn(CC2CC2)c2cnccc12

Procedure:
Starting material: 1H-Pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester, R5X=cyclopropyl-methylbromide; NH2A=2-aminothiazole
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[O:23]C(=O)C)=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4].O[Li].O>C1COCC1.CO.O>[F:33][C:29]1[CH:28]=[C:27]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:14]([CH:16]3[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]3[OH:23])=[O:15])[CH:11]([CH3:12])[CH3:13])[CH:8]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1OC(C)=O)C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3cccc(F)c3)sc2C(=O)O)C(C)C)C(O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
3[(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-(3-fluoro-phenyl)-thi-ophene-2-carboxylic acid methyl ester (30 mg, 0.063 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 2 mL) and then added 1N aqueous solution of LiOH.H2O (0.38 mL, 0.380 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 5-(3-fluoro-phenyl)-3-[(2-hydroxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-thiophene-2-carboxylic acid (Compound 44) (15 mg, 58%) as a white solid with two rotamers. 1H NMR (CDCl3, 400 MHz): δ7.50-7.25 (m, 3H), 7.06 (m, 2H), 6.25 (bs, 1H), 5.25 (s, 1H, minor), 4.87 (s, 1H, major), 4.13 (s, 1H, major), 3.87 (s, 1H, minor), 2.38-0.45 (m, 17H). ESI− (M−H): 418.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH2:5][CH2:4][CH:3]=1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19].C(C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2CCC=1)(=O)C.BrN1C(=O)CCC1=O>N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH2:5][CH:4]([CH2:19][C:18]([OH:21])=[O:20])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2=C(C(=O)c3ccccc31)C(O)=CCC2
Agent: CC(=O)C1=CCCC2=C1C(=O)c1ccccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CC1C=C(O)C2=C(C1)C(=O)c1ccccc1C2=O
Reaction time: 8 h

Procedure:
1-hydroxy-3,4-dihydroanthraquinone is reacted with 2 moles of acetic anhydride in pyridine for 15 hours. The mixture is poured into water, when 1-acetyl-3,4-dihydro-anthraquinone separates. It is collected, washed and dried at 80° C. and 2 Pa absolute (15 torr). The 1-acetyl-3,4-dihydroanthraquinone is reacted with 2 moles of N-bromosuccinimide while suspended in boiling carbon tetrachloride under reflux for 2 hours. 1-acetyl-3-bromo-3,4-dihydroanthraquinone is collected, dissolved in acetone and treated with ethyl 2-bromoacetate and excess copper powder, under reflux, for 2 hours. The ethyl ester of 1-acetoxy-3(carboxymethyl)-3,4-dihydroanthraquinone is collected and hydrolysed by standing overnight in N sodium hydroxide solution under nitrogen. The free acid, 1-hydroxy-3(carboxymethyl)-3,4-dihydroanthraquinone is then obtained on acidification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([C:30]2[S:31][C:32]([CH2:36]O)=[C:33]([CH3:35])[N:34]=2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:36][C:32]3[S:31][C:30]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([F:29])([F:27])[F:28])=[C:20]([F:19])[CH:21]=4)=[N:34][C:33]=3[CH3:35])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1CO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 0228434 A2] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain {6-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as light yellow gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:13][O-:14].[Mg+2].C[O-]>C1(C)C=CC=CC=1.CO>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]=1[CH:13]=[O:14]
Reactant: COCCOc1ccc(O)cc1
Reactant: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(2-methoxyethoxy)phenol in toluene (350 ml) was added to a solution of magnesium methoxide in methanol (8% by weight solution, 331 mls), under an atmosphere of argon. The reaction mixture was heated at reflux for 2 hours. Toluene (350 mls) was added and the reaction mixture distilled at atmospheric pressure until the internal temperature reached 92° C. A mixture of paraformaldehyde in toluene (300 ml) was added to the reaction mixture and the reaction mixture was heated at reflux for 3.5 hours. The mixture was cooled to ambient temperature and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with toluene (400 ml), washed with 2M aqueous hydrochloric acid (2×150 ml) and water (to pH 1). The residue was distilled under vacuum to give 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde as an oil (35 g), bp 104-130° C. [0.01 mm Hg]; NMR(CDCl3): 3.45(3H,s), 3.75(2H,m), 4.12(2H,m), 6.92(1H,d), 7.05(1H,d), 7.2(1H,dd), 9.84(1H,s) and 10.63(1H,s); m/z 197(M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.C1CCN2C(=NCCC2)CC1.Cl>O.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([NH:17][C:29]([NH:28][C:22]1[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][CH3:27])[N:23]=1)=[O:30])(=[O:15])=[O:16]
Reactant: CCCc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1ccc2nc(Cl)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.49 g, 1.78 mmol), phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.55 g, 2 mmol) and acetonitrile (5 ml) were introduced into a 25-ml eggplant type flask and stirred at room temperature, and DBU (0.31 g, 2 mmol) was added all at once thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water (50 ml) and adjusted to about pH 2 with dilute hydrochloric acid, whereby crystals were formed. The crystals were collected by filtration, washed with water, acetone and ether in this order and dried under reduced pressure to give the title compound as pale brown crystals. The yield was 0.71 g (89.5%).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH3:20])=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][N:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:45])[NH2:28])=[CH:25][CH:26]=4)[CH3:20])=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-N-me-thylaminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 73% of theory, C28H29N5O3S (515.64); Rf value: 0.29 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=516.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[O:22])[CH2:4][CH2:3]1.F[C:31](F)(F)[C:32](O)=[O:33].C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[O:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:22])=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:15][CH2:16]1)(=[O:33])[CH3:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To 40.0 mg (0.0546 mmol) of 5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide tris(trifluoroacetic acid salt) (as prepared in Example 16) suspended in 2 mL of anh THF was added 6.2 μL (0.0655 mmol) of acetic anhydride followed by 47.6 μL (0.716 mmol) of DIEA. After stirring for 20 min at RT, the mixture was poured into satd aq NaHCO3 (20 mL) and extracted with EtOAc (20 mL). The extract was dried (Na2SO4) and concentrated in vacuo and the resulting solid was chromatographed on a 2-g silica SPE column with 25-40% EtOAc-dichloromethane to afford 22.0 mg (92%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.59 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.79 (d, 1H, J=2.6 Hz), 6.72 (dd, 1H, J=8.9, 2.6 Hz), 3.77-3.80 (m, 2H), 3.62-3.64 (m, 2H), 3.11-3.17 (m, 4H), 2.98-3.01 (m, 2H), 2.73-2.76 (m, 2H), 2.15 (s, 3H), 1.83-1.86 (m, 2H), 1.52-1.62 (m, 1H), 1.46-1.56 (m, 2H) and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C24H29N5O3, 436.2 (M+H), found 436.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:7]=[C:8]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)=[N:10][CH:11]=1.C[Li].C([Li])CCC.[NH4+].[Cl-:43]>C1COCC1>[ClH:43].[CH3:31][O:30][C:26]1[CH:25]=[C:24]([S:23][C:8]2[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([CH:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[N:14]=3)=[N:10][CH:11]=[C:6]([O:5][C:4]3[CH:32]=[CH:33][CH:34]=[CH:2][CH:3]=3)[CH:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2Nc2nc(C3CCCO3)ns2)c1
Reactant: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(Sc2cc(Oc3ccccc3)cnc2Nc2nc(C3CCCO3)ns2)c1
Product: Cl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine (41 mg, 0.074 mmol) and THF (2 mL). The reaction was cooled to −78° C. and methyllithium (0.055 mL, 0.088 mmol) was added and stirred for 5 minutes. Butyllithium (0.035 mL, 0.088 mmol) was added and stirred for 5 minutes. The reaction was then poured into saturated aqueous NH4Cl and extract with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (35% ethyl acetate in hexanes) to afford the title compound (36 mg, 95%) after HCl salt formation. 1H NMR (d6-DMSO) δ 11.47 (bs, 1H), 8.30 (bs, 1 h), 7.59 (bs, 1H), 7.37 (m, 2H), 7.28 (t, 1H), 7.14 (t, 1H), 7.03 (d, 2H), 6.88 (m, 3H), 4.04 (t, 1H), 3.90-3.75 (m, 3H), 3.72 (s, 3H), 3.57 (m, 1H), 2.25 (m, 2H). Mass spectrum (apci) m/z=479.2 (M+H—HCl).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[ClH:39]>O>[ClH:39].[ClH:39].[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 76 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added 120 parts of a hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes at room temperature. Upon cooling in an ice-bath, the product is precipitated. It is filtered off, washed with 2-propanone and with 2,2'-oxybispropane, and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride.hydrate; mp. 237.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=O.[CH:16](OCC)=O.O.[NH2:22][NH2:23]>O1CCCC1.Cl>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([C:4]2[CH:3]=[CH:16][NH:23][N:22]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC=O
Reactant: NN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc[nH]n2)cc1
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
First, 3.18 g (79.4 mmol) of a 60% sodium hydride suspension in mineral oil was added in portions to a solution of 9.96 g (52.9 mmol) of 4-trifluoromethylacetophenone and 12.6 mL (158.76 mmol) of ethyl formate in 75 mL of anhydrous tetrahydrofuran at 0° C. The mixture was allowed to reach ambient temperature, at which an exothermic reaction occurred, which subsided in 5 min. After 1 h, the mixture was concentrated and the residue was triturated with diethyl ether to provide a tan solid in two crops. The solid was suspended in 1N hydrochloric acid and the resulting bright yellow solid was filtered and washed with water. The solid was dissolved in 150 mL of methanol and stirred at room temperature with 4.7 mL (96.9 mmol) of hydrazine hydrate for 3 h. Solvent was evaporated and the resulting solid was suspended in water, stirring for 18 h. The solid was filtered, washed with water, and dried under vacuum to provide 8.9 g (80%) of 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole as a yellow solid. 1H-NMR (DMSO-d6): δ 13.05 (br s, 1H), 7.99 (d, J=8 Hz, 2H), 7.8 (br s, 1H), 7.71 (d, J=8 Hz, 2H), 6.81 (s, 1H); ES-LCMS m/z 213 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=O)=[CH:4][CH:3]=1.[OH2:18].C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=[N:25][OH:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Reaction time: 0.08 h

Procedure:
15.45 g (60.2 mmol) of tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (Example 2A) were initially charged in 750 ml of ethanol and admixed with a solution of 225 ml of water and 9.38 g (120.4 mmol) of sodium acetate and stirred for 5 min. A solution of 225 ml of water and 8.36 g (114.4 mmol) of hydroxylamine hydrochloride was added and the mixture was stirred at RT for 4 h. At 20° C., the reaction mixture was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed twice with saturated sodium hydrogencarbonate solution and once with saturated sodium chloride solution. The organic phase was removed, dried over magnesium sulphate and concentrated at 20° C. on a rotary evaporator. 15.5 g (80% of theory) of the product were obtained in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OCC)(=O)C>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Yield: 93 %

Procedure:
A solution of (R)-2-(3-chlorophenyl)-2-hydroxyacetic acid (25 g, 133.69 mmol, 1.00 equiv.) in methanol (300 mL) and sulfuric acid (3 mL) was heated at reflux for about 16 hours, and then concentrated in vacuo. After the solution was poured into a water/ice mixture (200 mL), the pH value of the solution was adjusted to 9 with sodium carbonate. Standard extractive workup with ethyl acetate (2×100 mL), gave the title product as an off-white solid (24.8 g; yield=93%). 1H NMR (300 MHz, CDCl3) δ: 7.45 (s, 1H), 7.32 (m, 3H), 5.17 (d, J=4.5 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH:18]([CH3:22])[C:19](O)=[O:20])[CH3:2].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[CH3:35].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:19](=[O:20])[CH:18]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[S:7][C:3]=2[CH2:1][CH3:2])[CH3:22])=[CH:30][C:29]=1[CH3:35]
Reactant: COC(=O)CCc1ccc(N)cc1C
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C(=O)Nc1ccc(CCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid (0.35 mmol), 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.35 mmol), and DMAP (0.01 g, 0.082 mmol) in CH2Cl2 (5 mL) is added EDCI (0.08 g, 0.42 mmol). After stirring for 2 h at RT, the mixture is concentrated. The residue is redissolved in EtOAc, and the organics are washed with 1N HCl (1×), 2N NaOH (2×), water, and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>C(OCCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:15])[C:12]([Cl:14])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CCCCOCCCC
Product: O=C(Cl)C(=O)c1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 5-chloroindole (20 g, 0.13 mole) and dibutyl ether (230 mL) and cool to 5° C. and slowly add the oxalyl chloride (20.08 g, 0.16 mole) over 15 min while maintaining the temperature between 5° C. and 10° C. Warm to room temperature and stir for 1 hour to give a solid. Cool to 5° C. and stir for 15 minutes, collect the solid by filtration, wash with dibutyl ether, and dry under vacuum to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15]C=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:54]=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][N:54]=2)=[N:10][O:11][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reactant: OCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCCc2ccccc2)cn1
Temperature: 90 °C
Yield: 63.7 %

Procedure:
To a solution of [3-(4-hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (68 mg, 0.247 mmol), phenethyl alcohol (30 μL, 0.25 mmol)) and triphenylphosphine (136 mg, 0.52 mmol) in THF (1.5 mL) at 0° C. was added diethylazodicarboxylate (100 μL, 0.55 mmol) over 1.5 h. The reaction mixture was warmed to 90° C. for 62 h and cooled to rt. Volatiles were removed under reduced pressure and the crude product was dry-loaded onto silica gel. Chromatography provided [3-(5-phenethyloxy-pyridin-2-yl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (60 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([C:11]#[N:12])[C:6](OCC)=O)[CH3:2].[OH2:13].[NH2:14][NH2:15]>C(O)C>[NH2:12][C:11]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][NH:15][N:14]=1
Reactant: O
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1N

Procedure:
To a solution of ethyl (ethoxymethylene)cyanoacetate (10 g) in ethanol (100 ml), was added hydrazine monohydrate (2.87 ml), and the resulted mixture was refluxed for 12 h. The reaction mixture was evaporated under reduced pressure followed by addition of ether (50 ml), and 3-amino-4-ethoxycarbonylpyrazole was obtained as pale yellow crystals (7.68 g, yield 84%).