Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH:25]=1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: Nc1cccnc1
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)Nc1cccnc1

Procedure:
The title compound was prepared from 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid and pyridine-3-ylamine as describe in Example 88 and isolated as a yellow solid (0.085 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=2.27 Hz, 1H), 8.40 (d, J=4 Hz, 1H), 8.23 (d, J=4 Hz, 1H), 7.61 (s, 1H), 7.32-7.36 (m, 1H), 7.18 (d, J=2 Hz, 1H), 6.91-7.05 (m, 4H), 6.76 (d, J=2 Hz, 1H), 4.37 (t, J=7 Hz, 2H), 3.19 (t, J=7 Hz, 2H), 2.81 (s, 3H); MS (M+H)+=408.1; Rt=1.32 min; HRMS (M+H)+=408.13.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccccc3)n2)c1

Procedure:
Example 4 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [2-(benzyloxy)-4-fluorophenyl]boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC:
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>C(O)(=O)C>[N:12]1([CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCCC1CC(=O)N(CO)C1
Solvent: CC(=O)O
Product: CCCC1CC(=O)N(Cn2cnc3ccccc32)C1

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 1-(hydroxymethyl)-4-propyl-pyrrolidin-2-one a24 (2.5 mmol, 400 mg) and benzimidazole (1 eq, 2.5 mmol, 300 mg) in acetic acid (20 ml) was heated at reflux overnight. After cooling, acetic acid was removed under vacuum, and the crude product was purified by preparative chromatography on silicagel to give 1-(1H-benzimidazol-1-ylmethyl)-4-propyl-pyrrolidin-2-one 91 after recrystallization in diisopropylether (16%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=[C:9]([O:48][Si](C(C)(C)C)(C)C)[CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:29]([O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][C:11]1[CH:12]=[C:7]([OH:6])[CH:8]=[C:9]([OH:48])[CH:10]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cc(O)cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To an ice-cooled solution of Compound 44 (2.81 g, 3.44 mmol) in THF (30 ml), a solution of 1M tetrabutylammonium fluoride in THF (4 ml) was added. After completion of the addition, the ice bath was removed, and this was followed by stirring at room temperature for 1 hour. This was poured over water to stop the reaction, after which extraction from ethyl acetate was conducted. The organic phases were combined and washed with saturated brine, thereafter dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 1:1-1:2-1:3)) to yield Compound 45 (light-yellow oil 1.95 g, 96%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=O)=[CH:9][CH:8]=2)[CH2:4]1.Cl.[NH2:32][OH:33].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH2:14]/[C:15](/[C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[N:32]\[OH:33])=[CH:11][CH:12]=2)[CH2:6]1
Reactant: COC1CN(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC1CN(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)C1

Procedure:
In analogy to example 1, step 2, from (R)-3-[4-(3-methoxy-azetidin-1-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=416.3 ([M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]2[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=O)=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.O1CCCC1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]3[C:18]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=[CH:4][CH:3]=1
Reactant: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(SC)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1Cn2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 2-(4-fluorophenyl)-1-[4-methoxy-2-(2-methylsulfanyl-pyrimidine-4-carbonyl)pyrazolidine-1-yl]-ethanone, 48, (2.04 g, 5.22 mmol) in 1:1 dimethylformamide/tetrahydrofuran (30 mL) is added dropwise to a 0° C. suspension of sodium hydride (230 mg of a 60% dispersion in mineral oil, 5.75 mmol) in dimethylformamide (60 mL). After 2 hours at 0° C., the bright red solution is quenched by slow addition of a saturated aqueous solution of ammonium chloride (5 mL). The cold bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resultant residue diluted with ethyl acetate (175 mL). The mixture is washed with a saturated aqueous solution of ammonium chloride (150 mL). The aqueous layer is extracted with ethyl acetate (4×75 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified over silica gel (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 1.1 g (57% yield) of the desired product as an orange oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:15]1.[Cl-].[NH4+].C1C[O:29]CC1>CCCCCC.CCOC(C)=O>[OH:29][CH:18]([CH2:17][C:14]1([CH3:13])[CH2:15][CH2:16]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C1CCOC1
Reactant: CCOC(=O)CCC1(C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)CC1(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (1.9 mL, 13 mmol) in dry THF (20 mL) at 0° C. under inert atmosphere was added n-butyllithium (5.2 mL of a 2.5 M solution in hexane, 13 mmol) dropwise over a period of 5 min. The solution was cooled to −78 ° C. and ethyl 3-(1-methyl-cyclopropyl)propanoate (1.87 g, 12 mmol) was added dropwise over a period of 5 min. The solution was stirred at −78 ° C. for 1 h at which time (+)-camphorsulfonyloxaziridine (3.5 g, 15 mmol) was added all at once. The resulting suspension was stirred at −78 ° C. for 30 min and then allowed to warm to ambient temperature over 30 min. EtOAc (50 mL) and saturated aqueous ammonium chloride (25 mL) were added and the organic layer was separated and washed with water (20 mL), dried (MgSO4), and filtered. The solvents were removed under reduced pressure and the resulting oily solid was stirred in ether (15 mL) for 30 min. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography using a gradient elution of 10% to 15% EtOAc in hexanes to give ethyl 2-hydroxy-3-(1-methyl-cyclopropyl)propanoate as a colorless liquid. TLC Rf=0.5 (20% EtOAc-hexanes); HPLC RT=2.73 min (Method A); 1H NMR 400 MHz, CDCl3, 4.31 ppm (M, 1H)4.23 ppm (m, 2H), 2.65 ppm (d, J=6.1 Hz, 1H), 1.76 ppm (dd, J=4.2, 14.6 Hz, 1H), 1.54 ppm (dd, J=8.4, 14.6 Hz, 1H), 1.30 (t, J=8 Hz, 3H), 1.14 ppm (s, 3H), 0.42 ppm (m. 1H), 0.30 ppm (m, 3H)
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(Cl)c1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (22) (553 mg, 2.60 mmol) was treated with 3-chloroaniline (800 mg, 6.3 mmol) using method A to give 4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid as an off white solid. Yield: 382 mg (49%). 1H-NMR: 10.73 (s, 1H), 8.09 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.27 (t, J=8.5 Hz, 1H), 7.13-7.04 (m, 3H).
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1.[H-].[Na+].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC=CC=1>[CH3:21][O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1
Reactant: COS(=O)(=O)OC
Reactant: CC1=C2CCC(C)(O)CC(C)C2CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C1CC(C)(OC)CCC2=C(C)CCC12
Yield: 74 %

Procedure:
9.6 g of 6-hydroxy-1,6-dimethyl-4-methyl-2,3,3a,4,5,6,7,8-octahydroazulene in 300 ml of absolute benzene were heated to reflux for 15 hours with 4.8 g of sodium hydride (50% paraffin-containing paste, purified by washing with benzene). Then 95 ml of freshly distilled dimethyl sulphate were added at 40°. The mixture was stirred at reflux for a further 7 hours, cooled to 5°, treated with 20% citric acid solution and extracted with ether. The ethereal phase was washed with bicarbonate solution and water, dried in a conventional manner and concentrated under reduced pressure. The oily residue so obtained (12.5 g) was loaded onto 125 g of silica gel and by elution with hexane there were obtained 7.65 g (74%) of 6-methoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene which was then distilled in high vacuum; b.p.0.02 ca 55°; IR(film): νmax = 3090, 1640, 1450/40, 1370, 1252, 1120, 1080, 890, 835, 765/55 cm-1. The compound has a camphorous, woody odour.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])(=O)C.[Na+]>>[C:9]([CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])(=[O:11])[CH3:10]
Reactant: CC1CCC(=O)CC1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24 g of 40% boron trifluoride/acetic acid complex was cooled with ice and a mixture of 5.6 g of 4-methylcyclohexanone and acetic anhydride was added dropwise thereto. After stirring at room temperature for four hours, approximately 50 ml of a saturated aqueous solution of sodium acetate was added thereto and the obtained reaction mixture was heated under reflux for one hour. After cooling, the reaction mixture was extracted with ether, washed with an aqueous solution of sodium hydrogencarbonate and water and dried, and ether was distilled off. The total amount of the crude 2-acetyl-4-methylcyclohexanone thus obtained was subjected to the subsequent step as such.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[C:14]([C:18]1[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:21]2[O:22][P:23](Cl)[O:24][C:25]3[C:30]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][C:28]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:27][C:26]=3[C:20]=2[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:35]([C:28]1[CH:29]=[C:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]2[O:24][P:23]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]3)[O:22][C:21]3[C:40]([C:42]([CH3:44])([CH3:43])[CH3:45])=[CH:41][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][C:20]=3[C:26]=2[CH:27]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Product: CON1C(C)(C)CC(Op2oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c3cc(C(C)(C)C)cc(C(C)(C)C)c3o2)CC1(C)C

Procedure:
The title compound is prepared from 4-hydroxy-1-methoxy-2, 2,6,6-tetramethylpiperidine and 2,4,8,10-tetra-tert-butyl-6-chlorodibenzo [d,f][1,3,2]dioxaphosphepin according to the procedure of Example 1C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:40]1[C:48]2[N:47]=N[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:11]1[C:12]2[C:13](=[CH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:45][C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:48]=3[NH2:47])=[O:26])=[O:17])[C:14]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
6-(2-(9H-xanthen-9-ylidene)acetamido)hexanoic acid (351 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (335 mg, 76% yield) as a brown solid. LC-MS (m/z) 442 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](Cl)=[O:23])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22]([O:8][C@@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:23])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Step 2) and pyridine (0.18 kg, 2.28 mol) stirring at 65° C. The reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25° C. and stirred for a 14 hours. The solution was diluted with toluene (16 kg), washed with 5% aqueous sodium chloride (6.4 kg), then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:35][C:34]([C:36]([O:38]C)=[O:37])=[CH:33][C:9]=3[N:10]([CH2:28][C:29](OC)=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1COCC1>CO.C1COCC1.O.CC#N>[CH:1]1([C:7]2[C:8]3[S:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][C:9]=3[N:10]3[CH2:28][CH2:29][N:19]([C@H:20]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21]4)[CH2:18][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cn1c(-c2ccccc2CN[C@H]2CCN(C(C)C)C2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)N1CC[C@H](N2CCn3c(c(C4CCCCC4)c4sc(C(=O)O)cc43)-c3ccccc3C2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 6-cyclohexyl-5-[2-({[(3S)-1-isopropylpyrrolidin-3-yl]amino}methyl)phenyl]-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in MeOH/THF/water and LiOH monohydrate (1.04 eq.) was added to the solution. The mixture was left stirring at RT for 5 h. All volatiles were evaporated i. vac. and the residual material was dried i. vac. The crude material was redissolved in DMF, HATU (1.2 eq.) and DIPEA (3.6 eq.) were added and the mixture was left stirring overnight. All volatiles were evaporated i. vac. and the residual material was filtered with EtOAc/PE+1% NEt3 through silica gel. After evaporation of the solvents the crude product was dissolved in THF and 2M borane dimethylsulfide complex in THF (20 eq.) was added. After 1 h all volatiles were evaporated i. vac. and the residual material was dissolved in an excess of 1.25M HCl in MeOH. The solution was warmed to 70° C. and evaporated slowly to dryness. The crude residue was dissolved in dioxane and an excess of 1N aq. KOH-solution was added. The mixture was left stirring over night and then warmed for 2 h to 50° C. The product was then isolated by prep. RP-HPLC. After lyophilisation of the product fractions a colourless solid was obtained (42%). 1H-NMR (400 MHz, DMSO-d6, 330 K, mixture of atropisomers, δ) 7.90-7.88 (2s, 1H); 7.53-7.47 (m, 3H), 7.39-7.37 (2s, 1H), 4.59-4.48 (m, 1H), 3.91-3.42 (m, 5H), 3.30-3.18 (m, 1H), 3.10-2.67 (m, 2H), 2.60-2.51 (m, 3H), 2.33-2.15 (m, 2H), 2.03-2.00 (m, 1H), 1.85-1.82 (m, 1H), 1.74-1.65 (m, 3H), 1.59-1.43 (m, 2H), 1.36-1.10 (m, 10H); MS (ES+) m/z 492 (M+H)+; [α]D20−4.8° (c=1.0 in MeCN).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH:15]C(=O)C)=[N:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[CH3:4]>Cl>[OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)NC(C)(C)CO)s1
Agent: Cl
Product: CC(C)(CO)NS(=O)(=O)c1cnc(N)s1
Temperature: 80 °C
Yield: 72 %

Procedure:
A stirred suspension of 2-acetamido-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.68 g, 2.32 mmol) in 6N hydrochloric acid (20 ml) was heated for 2 h at 80° C., evaporated., and saturated NaHCO3 solution (30 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield the title compound (0.42 g, 72%) as a colorless oil. MS (ISP) 250.0 [(M−H)−].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH3:25][N:26]1CCCC1=O.N>C(OCC)(=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:25]#[N:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCCC1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c2ccc(Br)cc12
Agent: N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]cc(CCCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[3-[5-Bromo-1H-indol-3-yl]propyl]-1H-isoindole-1,3-(2H)-dione (8.43 g) and cuprous cyanide (3.2 g) were added to N-methyl-2-pyrrolidinone (20 ml) under a nitrogen atmosphere. The stirred mixture was heated to reflux over 25 min. and maintained at reflux for 45 min. It was then cooled to room temperature and poured onto ice-water (300 g). Concentrated aqueous ammonia (40 ml) and ethyl acetate (300 ml) were added and the mixture was stirred vigorously for 20 min. The brown organic layer was separated from the blue aqueous phase. The aqueous phase was then extracted with ethyl acetate (3×100 ml). The combined organic solutions were washed with water (3×100 ml) until the washings were colourless, dried (MgSO4) and evaporated in vacuo to afford a fawn solid (6.85 g), which was recrystallised from a mixture of isopropyl acetate (300 ml) and 2-propanol (100 ml) to afford the title compound as a pale fawn solid (5.2 g) m.p. 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:19](=[O:20])[N:18]([CH3:17])[C:4]2([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN=C=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 96.5 %

Procedure:
A solution of 100 g (0.43 mole) of 2-amino-5-chlorobenzophenone and 40 g (0.7 mole) of methyl isocyanate in 300 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 119.8 g (96% yield) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone as a white crystalline powder: mp 296°-298° (dec); 1H nmr (DMSO-d6), δ 2.66 ppm (s, 3H), 6.8-7.6 ppm (m, 8H) and 10.0 ppm (s, NH); 13C nmr (DMSO-d6) δ 86.6 ppm (for COH) and 151.4 ppm (for NHCO).