Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:5]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(=S)Nc2ccc(C)cc2C(N)=O)cc1
Yield: 91.7 %

Procedure:
To a stirred mixture of 3 g of 2-amino-5-methylbenzamide and 200 ml of ether was added dropwise, a solution of 3.7 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 30 minutes. After 24 hours the solid was collected, giving 6 g of N-[[[2-(aminocarbonyl)-4-methylphenyl]amino]thioxomethyl]-4-methylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([S:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH3:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:39][CH:38]=1
Reactant: CCS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 4-ethanesulfonyl-benzylamine (0.2 g, 1.06 mmol) to give 7-chloro-6-(4-ethanesulfonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[CH3:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(NN)ccc1I
Reactant: CC(=O)c1ccccc1
Product: CC(=NNc1ccc(I)c(C)c1)c1ccccc1

Procedure:
Analogously to the process described under Example 1A, 992 mg (4.0 mmol) of the compound from Example 6A and 721 mg (6.0 mmol) of acetophenone give 1.405 g (100% of theory) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:16])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C(O)C>[CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]3[S:15][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:16]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(-c2ccccc2)cs1
Temperature: 75 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (41 mg, 0.16 mmol) in 5 mL of ethanol was added 2-bromoacetophenone (33 mg, 0.16 mmol) and the reaction was heated at 75° C. overnight. After 16 hours, the reaction was cooled and concentrated and the crude product was purified by flash chromatography on silica gel loaded with CH2Cl2 and eluted with 2:1 hexanes/ethyl acetate followed by 1:2 hexanes/ethyl acetate to provide the title compound as a solid (32 mg, 94%). HPLC, tR, 3.54 min.(6 minute method); MS, m/z 350.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1([F:18])[C:7]([F:9])([F:8])[O:6][C:5]([F:11])([F:10])[C:4](F)(F)[N:3]1[C:14]([F:17])([F:16])[F:15].S(=O)(=O)=[O:20].S(=O)(=O)(O)O.FC1(F)OC(F)(F)C(=O)N(C(F)(F)F)C1=O>>[F:10][C:5]1([F:11])[O:6][C:7]([F:9])([F:8])[C:2]([F:18])([F:1])[N:3]([C:14]([F:17])([F:16])[F:15])[C:4]1=[O:20]
Reactant: O=S(=O)=O
Reactant: FC(F)(F)N1C(F)(F)C(F)(F)OC(F)(F)C1(F)F
Agent: O=C1N(C(F)(F)F)C(=O)C(F)(F)OC1(F)F
Agent: O=S(=O)(O)O
Product: O=C1N(C(F)(F)F)C(F)(F)C(F)(F)OC1(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 253 g. (0.85 mol) of perfluoro-(N-methyl-morpholine) in a 300 ml. autoclave is added 72 g. (0.9 mol) of sulfur trioxide. The vessel is sealed, heated and rocked at 120° C. for 6 hrs. The autoclave is then cooled to 25° C., vented to release volatile materials and the residue charged to a 500 cc. flask equipped with magnetic stirrer, dropping funnel, condenser and thermometer. A solution of 195 g. of 96% sulfuric acid and 5 g. of H2C is added dropwise with stirring. The temperature is kept below 50° C. After the sulfuric acid is added the mixture is heated and stirred at reflux (55°-60° C.) for four hours. Distillation yields a large fraction, 207 g., b.p. 48°-65° C./740 mm., which consists of 45% by weight perfluoror-N-methyl-3-oxo-morpholine (40% conversion) and 15% by weight of higher boiling products believed to include perfluoro-(N-methyl-3,5dioxo-morpholine). Isolation of the pure amide (b.p. 59°-60° C./740 mm.) can be accomplished by distillation through a 25-plate column.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOCC>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of 4-Bromo-phenyl-acetic acid (8.6 g, 40 mmol) in DMF (80 mL) is added K2CO3 (6.16 g, 44 mmol) followed by methyl iodide (2.8 mL, 45 mmol). The resulting mixture is stirred for 2.5 hours, then diluted with ether, washed with water and brine, dried over MgSO4 and concentrated to give 9.1 g of the title compound as an oil. This material is used without further purification. 1H NMR (CDCl3) d 3.58 (s, 2H), 3.69 (s, 3H), 7.13 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H). MS (EI) m/z 228/230 (M+) Br pattern.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(/C=C/CCC(=O)O)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CCCCC(=O)O)c(OC)c1
Reaction time: 8 h
Yield: 99 %

Procedure:
A 1-L hydrogenation flask was charged with 36.2 g of 5-(2,4-dimethoxyphenyl)-4-pentenoic acid (3a) and 400 ml of glacial acetic acid. The flask was flushed with argon and 2 g of (10% Pd/C) were added to the flask, which was then attached to the hydrogenator. The hydrogenation bottle was evacuated, and charged with hydrogen to 40 to 50 psi. The reaction was run overnight until no further hydrogen was being consumed. The solution was filtered through Cellite (diatomaceous earth). The solvent was evaporated, and the residue dried in vacuo. The yield was 99%. 1H NMR (DMSO-d6) δ: 12.01 (br s, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.49 (d, J=2 Hz, 1H), 6.41 (dd, J1=2 Hz, J2=8.2 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.45 (t, 2H), 2.20 (t, 2H), 1.47 (m, 4H).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14]([N:16]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18][CH2:17]2)=[O:15])([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3]>[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14]([N:16]2[CH:22]3[CH2:21][CH2:20][N:19]([CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: C=C(C)c1cccc(C(C)(C)NC(=O)N2CCN3CCC2CC3)c1
Agent: [Pd]
Product: CC(C)c1cccc(C(C)(C)NC(=O)N2CCN3CCC2CC3)c1
Yield: 59.7 %

Procedure:
Using general procedure F, N-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.305 mmol) and palladium, (20 mg, 20 wt. % on carbon) gave the title compound as an off-white solid (60 mg, 57%). 1H NMR (400 MHz, CDCl3) δ 7.28-7.21 (m, 3H), 7.11 (d, J=8.0 Hz, 1H), 4.71 (s, 1H), 4.02 (s, 1H), 3.66 (t, J=8.0 Hz, 2H) 3.15 (m, 7H), 2.06 (br s, 2H), 1.77 (s, 7H) 1.26 (d, J=4.0 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.8, 148.9, 148.5, 128.5.1, 124.7, 123.1, 122.4, 57.8, 56.0, 48.1, 46.4, 41.2, 34.5, 32.2, 30.4, 30.0, 29.9, 27.3, 24.3, 22.9 ppm. Purity: >91% UPLCMS (210 nm); retention time 0.74 min; (M+1) 330.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:29]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(=[O:31])=[O:30]>>[CH:22]1([C:17]2[CH:16]=[C:15]([C:14]3[C:4]4[C:3]([CH3:27])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:20]=[CH:19][C:18]=2[O:21][S:29]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([OH:37])=[O:36])(=[O:31])=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Product: Cc1sc2cc3ccccc3c(-c3ccc(OS(=O)(=O)c4cccc(C(=O)O)c4)c(C4CCCC4)c3)c2c1C
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.300 g, 0.805 mmol) and commercial 3-chlorosulphonylbenzoic acid (0.600 g, 2.71 mmol). Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 20% EtOAc/hexane followed by trituration with hexane gave 0.154 g (20%) of the title compound as a white solid, mp 120-128° C. 1H NMR (DMSO-d6) δ 1.23-1.36 (m, 2 H), 1.42-1.52 (m, 6 H), 1.55-1.69 (m, 3 H), 2.42 (s, 3 H), 2.96 (quintet, 1 H), 7.23-7.29 (m, 3 H), 7.33 (d, 1 H), 7.39 (ddd, 1 H), 7.47 (ddd, 1 H), 7.90 (t, 1 H), 7.97 (d, 1 H), 8.23 (dd, 1 H), 8.27-8.29 (m, 1 H), 8.37-8.39 (dt, 1 H), 8.50 (s, 1 H), 13.6-13.9 (br s, 1 H). IR (KBr) 3400, 2950, 1700, 1380 and 1190 cm-1. mass spectrum (-ESI) m/z 555 (M-H). Anal. Calcd. for C32H28,O5S2.0.65H2O: C, 67.62; H, 5.20; N, 0.00. Found: C, 67.60; H, 4.90; N, 0.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cccc(Cl)c1
Product: O=Cc1cc(F)c(Oc2cccc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chlorophenol.
Reaction SMILES: Cl.Cl.[C:3]([C:11]1[CH:41]=[CH:40][C:14]([CH2:15][N:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:22]3[N:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][CH:23]=3)[CH2:17]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:48][NH2:49].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>O>[C:3]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30](=[O:31])[NH:49][O:48][CH:43]4[CH2:44][CH2:45][CH2:46][CH2:47][O:42]4)=[CH:26][N:27]=3)[C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:17]2)=[CH:40][CH:41]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a mixture of (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (93 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (27 mg.), and 1-hydroxybenzotriazole (31 mg) in N,N-dimethyl for aide (1.6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (36 mg) at 4° C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (2 mL) and water (8 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (35 mg)
Reaction SMILES: [OH-].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26](Cl)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.[OH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O>[NH:10]1[CH2:9][CH2:8][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Reactant: OCCCN1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1nc(C2CCNCC2)c2ccc(OCCCN3CCCCC3)cc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Solid KOH (112 mg, 2 mmol) was added to a mixture of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 82 mg, 0.2 mmol), prepared as described in Example 3, and 3-hydroxypropylpiperidine (0.25 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and diluted with water. The mixture was extracted with DCM and the organic layer was drawn off and washed with water thrice, with brine once, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3 ML of 3M HCl/MeOH and the mixture was stirred at rt for 2 h and then concentrated in vacuo to afford crude 4-piperidin-4-yl-7-(3-piperidin-1-yl-propoxy)-quinazoline.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[K].[CH2:20]([NH:27][S:28](=[O:31])(=[O:30])[NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:18][C:6]1[N:5]=[C:4]([NH:29][S:28](=[O:30])(=[O:31])[NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=[CH:2][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[Cl:17]
Reactant: NS(=O)(=O)NCc1ccccc1
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Agent: [K]
Product: COc1ccc(Cl)c(Oc2cnc(NS(=O)(=O)NCc3ccccc3)nc2Cl)c1
Yield: 47 %

Procedure:
Benzylsulfamic acid [6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidinyl]-amide (0.7 g) was prepared from 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine (1 g) and benzylsulfamic acid amide potassium salt (1.21 g) according to the procedure described in Referential Example 15. LC-MS: tR=5.13; [M+H]+=456.91.
Reaction SMILES: Cl.[CH2:2]([NH:10][NH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([NH2:17])(=[O:16])[C:13]([CH3:15])=O.O.O.O.C([O-])(=O)C.[Na+]>O>[CH2:2]([NH:10][N:11]=[C:13]([CH3:15])[C:12]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCCc1ccccc1
Reactant: CC(=O)C(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NNCCc1ccccc1)C(N)=O

Procedure:
3.4 g. Phenethylhydrazine hydrochloride are dissolved in 10 ml. water and mixed with 1.7 g. pyruvamide dissolved in 50 ml. water. 2.1 g. sodium acetate trihydrate are added thereto and the reaction mixture well shaken up. 2-(Phenethylhydrazono)-propionamide crystallizes out. It is filtered off and recrystallized from a mixture of cyclohexane and toluene. The yield is 2.0 g. (50% of theory); m.p. 78° C. (decomp.).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(C=CC2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCC2CCCCC2)cc1

Procedure:
The intermediate from Example 16, N-(p-cyclohexylvinylphenethyl)phthalimide (9.0 g) and 10% palladium on charcoal (0.9 g) in ethyl acetate (700 ml) is shaken with hydrogen at 3 atmospheres pressure over 7 hours. The mixture is filtered and the filtrate concentrated to dryness at reduced pressure to give N-[p-(2-cyclohexylethyl]-phenethyl]-phthalimide, m.p. 135°-138° after recrystallization from ethanol. The phthalimide (5.75 g) is added to a mixture of hydrazine hydrate (1.6 g) in methanol (100 ml) and heated under reflux for 18 hours. The mixture is concentrated to dryness at reduced pressure, made basic with cold concentrated aqueous potassium hydroxide and extracted with ethyl acetate. The organic extract is washed with water, then brine, dried over sodium sulphate and concentrated to dryness at reduced pressure to give the desired amine as an oil which gradually solidifies on standing.
Reaction SMILES: FC1C=CC(O)=CC=1.FC(F)(F)C1C=C(O)C=CC=1.[OH:20][CH:21]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1)[CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[S:26]([CH3:29])(=[O:28])=[O:27]>>[OH:20][CH:21]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:50])[F:51])[CH:44]=1)[CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)COc1cccc(C(F)(F)F)c1)S(C)(=O)=O
Agent: Oc1ccc(F)cc1
Agent: Oc1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1cccc(C(F)(F)F)c1

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step D, the p-fluorophenol is replaced by an equimolar amount of 3-trifluoromethylphenol. The product of Step D is thus ethyl 7-{N-[4-hydroxy-5-(3-trifluoromethylphenoxy)pentyl]methanesulfonamido}heptanoate. The subsequent hydrolysis step yields 7-{N-[4-hydroxy-5-(3-trifluoromethylphenoxy)pentyl]-methanesulfonamido}heptanoic acid (E).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[N:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1cnnc2c1C(=O)CC(c1ccsc1)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Yield: 96.7 %

Procedure:
To a mixture of 4-methyl-7-(thiophen-3-yl)-5,6,7,8-tetrahydrocinnolin-5-one (0.195 g) and aminoguanidine hydrochloride (94 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(thiophen-3-yl)-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 130) (0.26 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: Cc1cc(OC(F)(F)F)ccc1C(=O)O
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
795 mg (3.61 mmol) of 2-methyl-4-(trifluoromethoxy)benzoic acid are heated under reflux with 4 ml (54.8 mmol) of thionyl chloride and one drop of DMF for 30 minutes. After cooling, the reaction solution is introduced slowly dropwise into an ice-cooled concentrated aqueous ammonia solution. The resulting precipitate is collected by suction filtration, taken up in 30 ml of water and stirred at 60° C. for 1 h. The mixture is allowed to cool and the solid is collected by filtration and dried under vacuum. Yield 562 mg (71% of theory).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:7]=1)=[O:5])C>CO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:6]([C:4]([OH:5])=[O:3])=[N:7]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCCC2
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)c3c2CCCC3)cc1

Procedure:
A solution of 1-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester in methanol (50 ml) was heated at reflux temperature for one hour, cooled, concentrated in vacuo, diluted with water, and acidified. The precipitate was filtered to yield the title compound (0.360 g). An analytical sample (m.p. 233°-234° C.) was obtained from methylene chloride-hexane solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=O.ClC1C=CC(OC)=CC=1.C1(C)C(C(Cl)=O)=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:41](OCC)(=[O:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].N12CCCN=C1CCCCC2>ClC(Cl)C(Cl)Cl>[CH2:46]([O:45][C:43]([C:42]1[C:41](=[O:48])[O:17][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=2[C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:44])[CH3:47]
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)CC(=O)OCC
Agent: COc1ccc(Cl)cc1
Agent: Cc1ccccc1C(=O)Cl
Agent: [Al+3]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)C(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc(Cl)ccc2oc1=O

Procedure:
A mixture of 5-Chloro-2-hydroxy-2'-methylbenzophenone [prepared by reaction of 4-chloroanisole with ortho-toluoyl chloride in 1,1,2,2,-tetrachloroethane in the presence of aluminum chloride (150° C., 7 hours): melting point 65°-66° C.](71.9g), diethyl malonate (70 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4 ml) was stirred at 170° C. for 6 hours. The reaction mixture was purified by silica gel column chromatography (hexane) to yield 6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (73.2 g).