Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH:32]1([NH:36][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:22][CH:23]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.091 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added cyclobutylamine (94 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 26.3 mg of the title compound (59%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(NC1CC1)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94°-96° C. 1-(Phenylmethyl)-N-cyclopropyl-3-pyrrolidine-methanamine
Reaction SMILES: [H][H].Cl[C:4]1[N:9]=[C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16]>CO.[C].[Pd]>[N:9]1[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=12
Reactant: [H][H]
Reactant: COC(=O)c1cc2c(nc1Cl)CCCCC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2c(c1)CCCCC2
Yield: 100.2 %

Procedure:
After suspending 10% palladium-carbon (600.0 mg) in methanol (15.0 ml), the suspension was stirred at room temperature for 30 minutes in an atmosphere of hydrogen. A methanol solution (30.0 ml) of methyl 2-chloro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.00 g, 12.5 mmol) was added to the reaction solution and stirred at room temperature for 18 hours in an atmosphere of hydrogen. After removing the catalyst by filtration, the thus obtained residue was washed with methanol, the solvent was evaporated under reduced pressure and then the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (2.57 g, quantitative) as white powder
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][C:51]([OH:53])=O.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.CCN(C(C)C)C(C)C>[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:51](=[O:53])[CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:65][CH2:66]1)=[O:60]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCN(C(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of HBTU (1.90 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (1.95 mg, 0.005 mmol) in DMF (0.05 ml) and DIEA (0.0022 ml). The mixture was stirred at room temperature for 30 min then a solution of 1-(2-furoyl)piperazine (0.90 mg, 0.005 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 18 h at room temperature then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=553.4
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.C(S[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])(C)(C)C>O1CCCC1>[C:23]([S@@:21]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)S[S@](=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
n-BuLi (13.59 mL of 2.5 M, 33.97 mmol) was added dropwise to a solution of 4-bromobenzoic acid (3.41 g, 16.98 mmol) in tetrahydrofuran (31 mL) held at −78° C. The resulting mixture was stirred for 0.5 hours at −78° C. and 2-[(S)-tert-butylsulfanylsulfinyl]-2-methyl-propane (3.00 g, 15.4 mmol) in tetrahydrofuran (31 mL) was added slowly to the mixture. The mixture was allowed to stir for 0.5 hours at −78° C., before the reaction was allowed to warm up to room temperature. The reaction was quenched with water (50 mL) and the mixture was washed with ethyl acetate (3×30 mL). The aqueous layer was acidified with hydrochloric acid and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the filtrate was purified by silica gel chromatography utilizing a gradient of 0-100% ethyl acetate in hexane to yield to yield (S)-4-(tert-Butylsulfinyl)benzoic acid (770 mg, 22%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:1][C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[N:7]([CH3:11])[N:8]=[N:9][C:10]3=2)[N:12]=1
Reactant: Cn1nnc2c(N)c(N)ccc21
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1nnc2c3nc(O)c(O)nc3ccc21
Yield: 90.8 %

Procedure:
A solution of 4,5-diamino-1-methylbenzotriazole (1.2 g, 7.4 mmol) and oxalic acid dihydrate (1.2 g, 9.6 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h and allowed to cool. The resulting precipitate was collected by filtration and washed with water and ethanol to give 1.46 g (91%) of the title compound; m.p.>300° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6) 4.32 (s, 3H, CH3)), 7.33 (d, J=9 Hz), 1H, ArH), 7.55 (d, J=g Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.67 (broad s, 1H, OH).
Reaction SMILES: FC(F)(F)C(O)=O.C(=O)([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[CH:29]=[C:28]([O:31][CH3:32])[C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[CH:26][C:25]=3[C:24]3[C:42]([CH3:45])=[N:43][NH:44][C:23]=3[N:22]=2)=[CH:17][CH:16]=1)OC(C)(C)C.[ClH:47]>O1CCOCC1>[ClH:47].[CH3:45][C:42]1[C:24]2[C:25]3[CH:26]=[C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:28]([O:31][CH3:32])=[CH:29][C:30]=3[C:21]([C:18]3[CH:17]=[CH:16][C:15]([OH:14])=[CH:20][CH:19]=3)=[N:22][C:23]=2[NH:44][N:43]=1
Reactant: COc1cc2c(-c3ccc(OC(=O)OC(C)(C)C)cc3)nc3[nH]nc(C)c3c2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-{1-methyl-7-(methyloxy)-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl}phenyl carbonate trifluoroacetate (32 mg, 0.049 mmol) was taken into 4 N HCl in dioxane and the mixture was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in water, frozen, and lyophilized. 4-(1-methyl-7-(methyloxy)-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrochloride was isolated as a solid (13.0 mg, 0.028 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ9.71 (br m, 2H), 7.59 (d, 2H), 7.54 (d, 2H), 6.94 (m, 2H), 4.18 (d, 2H), 3.76 (s, 3H), 3.04-2.96 (m, 2H), 2.81 (s, 3H), 2.82-2.74 (m, 2H), 2.15 (m, 1H), 2.04 (br d, 2H), 1.67-1.61 (m, 2H); MS (EI) for C25H28N4O3: 433 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[C:32]1=[O:49])[CH3:30]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:49])[N:31]([CH2:29][CH3:30])[CH2:39]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5Cl)ncc34)ccc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described in Example 52, Step 8 starting from 6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=466.1.
Reaction SMILES: [Cl:1][C:2]1[C:7](C(O)=O)=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[N-:20]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[NH2:20][C:7]1[C:6]([F:11])=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Temperature: 55 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (step-5 of Intermediate-51, 1.0 g, 3.48 mmol) in conc. sulphuric acid (10.0 mL) was added sodium azide (0.271 g, 4.18 mmol). The reaction mass was stirred at 50-60° C. for 18 h. The reaction mass was quenched in ammonia solution (cold) and solid obtained was filtered and suck dried to afford 0.570 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 4.21 (d, J=5.7 Hz, 2H), 5.30 (s, 2H), 6.39 (t, J=7.8 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 7.98 (m, 1H); MS (m/z): 259.12 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[C:22]([F:29])[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2F)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (83 mg, 94%), MS (ISP) m/z=354.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])[CH3:34])=[CH:28][CH:27]=1)[CH2:13][C:14]1[N:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:16]=[CH:17][N:18]=1)C.Cl>O1CCOCC1>[C:4]([CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:13][C:14]1[N:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][N:18]=1)[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]([CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:40][CH2:41][CH3:42])[CH2:43][CH2:44][CH3:45])[CH3:34])=[CH:30][CH:31]=1)([OH:46])=[O:3]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2nccn2CC(=O)OCC)Cc2nccn2CC(=O)OCC)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2nccn2CC(=O)O)Cc2nccn2CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 139.5 %

Procedure:
The compound (34.1 mg) obtained in Example 86-1 was dissolved in dioxane (1.0 ml) and added with concentrated hydrochloric acid (500 μl) at room temperature and the whole was stirred at an outside temperature of 100° C. for 4 hours. After completion of the reaction, the resultant was concentrated and evaporated to dryness under reduced pressure, thereby obtaining a hydrochloride (43.4 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[CH2:18][CH3:19]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:22]([O:21][C:17](=[O:20])[CH2:18][CH3:19])[C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCC(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (44) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino propanoate according to Scheme 2. (1.09 g, 68%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.16-8.37 (2H, m), 8.00-8.15 (2H, m), 3.46 (3H, s), 2.61 (2H, q, 7.5 Hz), 1.29 (9H, s), 1.15 (3H, t, 7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11]
Reactant: CI
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, methyl iodide (1.92 mL, 31 mmol) was added and further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 4.9 g (74%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 3.52 (s, 3H), 7.38 (d, J=8.6 Hz, 1H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)(O)[C:28]#[N:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:28]#[N:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(O)C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.2 %

Procedure:
To a solution of 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (990 mg, 2.75 mmol), acetone cyanohydrin (913 mg, 10.73 mmol) and Ph3P (2.5 g, 9.63 mmol) in THF (25 mL) was added DIAD (2.2 g, 10.94 mmol) in THF (10 mL) over 5 hours at 0° C. and the resulting mixture was stirred for another 72 hours at room temperature. Standard work-up and purification afforded 4-[cyano-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (539 mg, 53%) as a white foam.
Reaction SMILES: Cl[C:2]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([Cl:17])(=[O:16])=[O:15])=[O:3].[CH3:18][OH:19]>C(Cl)(Cl)Cl>[CH3:18][O:19][C:2]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([Cl:17])(=[O:15])=[O:16])=[O:3]
Reactant: CO
Reactant: Cc1ccc2c(S(=O)(=O)Cl)c(C(=O)Cl)sc2c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc2cc(C)ccc2c1S(=O)(=O)Cl

Procedure:
Prepared analogous to Example 1(c) from 2-chlorocarbonyl-6-methyl-benzo[b] thiophene-3-sulfonic acid chloride and methanol in the presence of chloroform.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:17]
Reactant: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(CC)CC(O)c2cc(C#N)ccc2O1
Yield: 101.3 %

Procedure:
To a solution of 2,2-diethyl-3,4-dihydro-4-oxo-2H-1-benzopyran-6-carbonitrile (2.29 g) in a mixture of methanol (23 ml) and tetrahydrofuran (5 ml) was added sodium borohydride (0.37 g) at ambient temperature. The reaction mixture was stirred for an hour at the same temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methanol and methylene chloride (1:20) as an eluent to give 2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (2.34 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17].Cl>CC(OC)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of ethyl trifluoroacetate (7.95 ml, 1.1 eq) in MTBE (125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml, 1.2 eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was added portionwise and the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid (40 ml) was added cautiously and the organic phase separated, washed with brine and dried (Na2SO4) to give an orange solid. The orange solid was recrystallised from hot isopropanol to give the title compound as a yellow crystalline solid (11.25 g, 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([NH:17][C:18]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCN=C=O
Reactant: NC1CCCc2sccc21
Product: CCCCCCNC(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react with n-hexyl isocyanate to give 1-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 122° C. to 124° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].C1CCCCC1.[OH-].[Na+:39]>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:39]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to cyclohexane (60 ml) and the slurry was heated to reflux. A solution of NaOH (1 eq.) in MeOH (3 ml) was added to the slurry solution which became clear. After 15 min. a precipitate formed. After another hour, the mixture was cooled to room temperature and cyclohexane (40 ml) was added. The mixture was stirred over night. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried at 50EC in a vacuum oven for 24 h to yield 2.73 g (90%) of amorphous fluvastatin sodium.
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16](O)[CH2:17][CH3:18]>O>[CH2:16]([Ru:6]([CH:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:17][CH3:18]
Reactant: CCCO
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCC[Ru](C1C=CC=C1)C1C=CC=C1
Temperature: 120 °C
Yield: 19 %

Procedure:
8.0 g of bis(cyclopentadienyl)ruthenium, 3.0 g of aluminum chloride, and 80 g of polyphosphoric acid were mixed. The mixed solution was heated to 100° C. under a nitrogen atmosphere, to which 4.0 g of n-propyl alcohol was added dropwise over 30 minutes, and then the mixture was heated to 120° C. to carry out the reaction for 4 hours. After the reaction was completed, hot water was added to the solution to remove the polyphosphoric acid, and then distillation treatment gave 1.8 g of n-propylcyclopentadienyl(cyclopentadienyl)ruthenium.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2C)[C:9]2[C:8](=[O:21])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.Cl.NC(C1C(=O)CCCC=1NC1C=CC=C(C(F)(F)F)C=1)C1C=CC(C#N)=CC=1[Cl:43]>>[Cl:43][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[CH:10]1[C:9]2[C:8](=[O:21])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2](=[O:1])[NH:11]1)[C:16]#[N:17]
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Cl)c1
Agent: Cl
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Cl)c1

Procedure:
The title compound is prepared in analogy to 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55), using 4-(amino(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methyl)-3-chloro-benzonitrile hydrochloride (intermediate 54, 620 mg, 1.36 mmol) as starting material. Yield: 191 mg; ESI mass spectrum [M+H]+=446; Retention time HPLC: 0.65 min (X012_S01).