Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[Cl:13][C:14]1[CH:45]=[CH:44][C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=2[C:42]#[CH:43])=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:19])([C:4]2[N:3]([CH3:7])[C:2]([SH:1])=[N:6][CH:5]=2)[C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:33]=[CH:42][CH:43]=[C:36]([C:35]#[C:34][Si:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=2)=[CH:44][CH:45]=1
Reactant: Cn1ccnc1S
Reactant: C#Cc1c(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3C)cnc1S
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved in anhydrous THF (200 mL) under an atmosphere of dry N2. The solution was cooled to −78° C. and a solution of tert-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0° C. After a yellow precipitate formed, the solution was cooled to −78° C. and a solution of 6-(4-chloro-benzoyl)-1-methyl-4-(3-trimethylsilanyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mmol) in anhydrous THF (25 mL) was added. After 30 minutes, the solution was warmed to 0° C. and stirred at this temperature for 1 hour. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride (NH4Cl) and then partitioned between DCM and water. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoate (0.43 g, 1.05 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred for 2 hour at ambient temperature. Removal of all volatiles under reduced pressure gave 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid as an oily residue (0.43 g, quant.), which was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]([O:26]CC)=O)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]([NH2:29])=[O:26])[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2ccccc2n1
Reactant: N
Solvent: O
Product: NC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture compound 3 (0.2 g) and NH3 (7N in MeOH, 10 mL) was heated to 50° C. for 14 hours. After cooling to room temperature, the reaction was titrated with water, and the solid was collected, washed with water and dried to obtain compound 5 as a white solid (0.11 g, yield 60%): 1H-NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, 8.3 Hz), 8.25 (d, 114, 8.3 Hz), 8.15 (br, 1H, NH), 8.01 (dt, 1H, 1.3 & 8.1 Hz), 7.86 (d, 211, 8.9 Hz), 7.73 (dt, 1H, 1.3 & 8.1 Hz), 7.39-7.44 (m, 2H), 7.13-7.23 (m, 5H), 5.99 (br, 1H, NH); LC/MS: m/z=342.5 [M+H]+ (Calc: 341.4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([F:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([F:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[F:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 76 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), 2,6-difluoro-4-nitrophenol (1.37 g) and triphenylphosphine (2.67 g) in dichloromethane (30 ml) was added dropwise diethyl azodicarboxylate (1.57 ml) in an ice bath and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=6/1 as an eluant to give the desired compound (2.13 g, yield 76%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:3]=12.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:26][NH:27][C:28]([NH2:30])=[S:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:13])=[CH:10][C:3]=12
Reactant: O=C(O)c1cc2c(Cl)cncc2s1
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1cc2c(Cl)cncc2s1
Temperature: 70 °C

Procedure:
4-Chlorothieno[2,3-c]pyridine-2-carboxylic acid (4.2 g, 19.7 mmol) was dissolved in 110 mL DMF in a round bottom flask. To this flask was added CDI (7.68 g, 47.4 mmol). After the flask was heated at 70° C. for 30 minutes, thiosemicarbazide (4.32 g, 47.4 mmol) dissolved in 5 mL DMF was added and the resulting mixture was heated at 70° C. for 30 minutes. After removing the DMF under reduced pressure, the remaining residue was mixed with 50 mL 1N HCl. After filtration and washing with water, the product was dried in a vacuum oven at 80° C. for 4 hours. The resulting product (6.0 g) was used directly in the next step. LCMS (API-ES) m/z (%): 287.1 (100%, M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)O.[ClH:14].S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[Cl:14][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:3][N:2]([CH3:13])[CH3:1]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCC(Cl)c1ccccc1

Procedure:
(+-)3-dimethylamino-l-phenyl-1-propanol (10) (19 g) was dissolved in CH2Cl2 (200 ml). The solution was saturated with HCl (g). Thionyl chloride (17 ml) was added dropwise over 20 min. resulting in slight reflux. Subsequental reflux for 5 h resulted in the formation of a precipitate. Cooling and evaporation of the reaction mixture resulted in a yellowish crystalline mass, which was rinsed by several washings with acetone, resulting in colourless crystals of the title compound identified by 1H NMR.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>>[C:7]1([CH:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(c1ccccc1)n1cncn1
Yield: 43 %

Procedure:
A mixture of (RS) methyl 2-bromo-2-phenylacetate (25 g), 1,2,4-triazole (8.28 g) and potassium carbonate (16.5 g) in aetonitrile (200 ml) was refluxed for 3 hours, cooled evaporated under reduced pressure and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic extracts were washed with water, extracted twice with 2M hydrochloric acid and the combined acid extracts, after washing once with ether, were basified with solid potassium carbonate and extracted with ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as a yellow oil (10.2 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
First, 17.24 g of 4-chlorophenylacetic acid was dissolved in 200 ml of ethanol, to which a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The residue was poured into water and extracted with ethyl acetate, and the organic layer was dried and then concentrated. The residue was subjected to silica gel chromatography, which afforded 19.0 g of ethyl 4-chlorophenylacetate.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:19])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=1)C.[CH2:20](N)[CH2:21][NH2:22]>CO>[ClH:1].[NH:22]1[CH2:21][CH2:20][N:19]=[C:5]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=N)COc1cccc(NS(C)(=O)=O)c1
Reactant: NCCN
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Yield: 20.2 %

Procedure:
2-(3-Methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride (0.8 g) was suspended in 12 ml of absolute methanol (MeOH) and treated with 0.16 g of ethylene diamine. After 8 hours at room temperature the solvent was evaporated. The residue was purified by silica gel chromatography eluting with methanol:dichloromethane:ammonium hydroxide (16:84:0.1). Conversion to the hydrochloride salt by addition of 1.0M hydrogen chloride in ether gave 0.16 g of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl]methanesulfonamide hydrochloride, mp 183-187° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:41])([F:40])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[N:27]=1>>[F:40][C:25]([F:24])([F:41])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([NH:21][CH2:20][C:14]2([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=4)[N:10]=3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:35])[N:27]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccc(C(F)(F)F)cc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccc(C(F)(F)F)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 19 %

Procedure:
This compound was synthesized from (4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (9 mgs, 19% yield). 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.00 (m, 2H), 7.65-7.58 (m, 4H), 7.36 (s, 1H), 4.02-3.78 (m, 4H), 3.74 (m, 2H), 2.30 (m, 2H), 2.05 (m, 2H). MS (ESI) m/z: Calculated for C26H20F6N4O3S: 582.12. found: 583.1 (M+H)+.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[C:39](=[O:55])[CH:38]=[C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=3)[CH:42]=[N:41]2)=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Yield: 83 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 7a) instead of preparation 1c.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:15]([C:13]1[CH:12]=[CH:11][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH:14]=1)(=[O:17])[CH3:16]
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccn(S(=O)(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
A mixture of 41.4 g of 1-(phenylsulfonyl-1H-pyrrole, prepared as described above, and 17.16 g of acetyl chloride in 200 ml of dichloroethane was added to a suspension of 32 g of aluminum chloride in 200 ml of dichloroethane. The reaction was stirred for one hour, poured onto a mixture of ice and concentrated hydrochloric acid and extracted several times with ether. The extracts were combined and evaporated. The residue was triturated with ether and the solid collected, giving 39 g of 3-acetyl-1-(phenylsulfonyl)-1H-pyrrole.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=2)[N:4]=1)[CH3:2].[Br:19]Br.O>C(O)(=O)C>[Br:19][CH:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)c1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Yield: 86.9 %

Procedure:
To a solution 2-ethyl-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (300.0 mg, 1.13 mmol) in glacial acetic acid (10 ml) cooled in an ice bath was added dropwise a solution of bromine (0.39 g, 2.26 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. Evaporated acetic acid and then water was added to the solution and the mixture was extracted with dichloromethane. The organic layer was washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×10 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% ethyl acetate in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (Yield 339 mg, 87.2%). 1H NMR (400 MHz, CDCl3): δ 2.13 (d, 3H, J=5.31 Hz), 3.04 (s, 3H), 3.71 (s, 3H), 5.05 (m, 1H), 7.81 (d, 1H, J=7.58 Hz), 8.16 (d, 1H, J=7.58, Hz), 8.80 (s, 1H). MS m/z calc. 343.98, found (ESI); 344.8 (M+1)+. Retention time 3.06 minutes.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](N)=[O:11])=[N:2]1.[OH-:13].[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:11])=[O:13])=[N:2]1
Reactant: NC(=O)c1nsc2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1nsc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzo[d]isothiazole-3-carboxylic acid amide (5.05 mmol) in MeOH (100 mL) is treated with an aqueous NaOH solution (10 M, 10.0 mL) and heated to reflux for 16 h. The mixture is cooled to RT, concentrated in vacuo, made acidic by addition of hydrochloric acid (pH<2) and kept for 2 h at 0° C. The obtained precipitate is filtered off and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.73 min; [M+H]+=180.0.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2ccccc2)c1
Yield: 65 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 305 mg of 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=76° C.). Yield=65% over the two steps.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.[C:12]1([CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(#N)C>C(Cl)Cl>[C:12]1([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[O:25])=[CH:27][CH:28]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1nc(C(=O)O)cs1)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 70 %

Procedure:
2-Amino-4-thiazolecarboxylic acid ethyl ester (6.85 g, 39.8 mmol) was allowed to react with 4-phenylmethoxybenzoyl chloride (10.72 g, 43.8 mmol) according to the procedure in Example 1. The reaction was completed in 18 hours. After workup and flash chromatography on silica gel eluting with 1-7% acetonitrile in methylene chloride, the ethyl ester of 2-[[4-phenylmethoxybenzoyl]amino]-4-thiazolecarboxylic acid was obtained (70% yield) and was hydrolyzed to the corresponding acid with 1.0N NaOH as described in Example 1.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH:5]([OH:9])([CH2:7][CH3:8])[CH3:6]>>[CH:2]([O:9][CH:5]([CH2:7][CH3:8])[CH3:6])([CH2:3][CH3:4])[CH3:1]
Reactant: C=CCC
Reactant: CCC(C)O
Product: CCC(C)OC(C)CC

Procedure:
From the recycle, a 76% residual gas containing 95.2 grams of n-butenes (1.7 moles) and 30.4 grams of n-butene (0.52 mole) was removed per hours, was depressured to normal atmospheric pressure in the second separator and was discharged. In the second separator 140 grams (1.9 moles) of secondary butyl alcohol and 0.7-1.4 grams of di-sec. butyl ether were obtained per hour after removing the C4 -components in the form of a 77 to 89% crude alcohol still containing 10-22% water. The space-time yield of secondary butyl alcohol was 1.6 moles per liter of catalyst an hour, the selectivity being more than 99%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13](OCC)=[O:14])[CH:11]=[CH:12][C:6]=2[O:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(Cl)Cl>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(COC)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC1Cc2cc(CO)ccc2O1
Yield: 64 %

Procedure:
To an anhydrous solution of 2.66 g (11.26 mmole) ethyl 2-methoxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 15 ml tetrahydrofuran was added, in portions with stirring under nitrogen, 426 mg (11.26 mmole) lithium aluminum hydride and the mixture was stirred at room temperature for 2.4 hours. The reaction was quenched by cautious, dropwise addition of water, then acidified with 1N hydrochloric acid. The volatiles were evaporated and the residue taken up in water and extracted with ethyl ether, washing the extracts with brine. After drying over anhydrous magnesium sulfate and evaporation of solvent 1.674 g of oil was obtained. This crude product was dissolved in a small amount of methylene chloride and purified by column chromatography on silica gel to afford 1.40 g of product which was used as starting material in the procedure of Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH2:22][CH3:23])[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH2:22][CH3:23])[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 50 mg (88% yield, 3 steps) of 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butan-1-amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:10]=1[NH:11][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1OCc1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Synthesis of the compounds of general class III begins with the reaction of 2-amino4-chloro-5-nitrophenol at 0-50° C., preferably at room temperature, with benzyl bromide in the presence of potassium carbonate and tetra-N-butylammonium iodide in DMF to give 2-benzyloxy-5-chloro-4-nitroaniline in 56% yield. Subsequent reaction of 2-benzyloxy-5-chloro-4-nitroaniline (25-80° C.), preferably refluxing, with benzoyl chloride in the presence of triethylamine provided N-(2-benzyloxy-5-chloro-4-nitrophenyl)benzamide in 85% yield. Reaction of N-(2-benzyloxy-5-chloro4-nitrophenyl)benzamide with sodium dimethyl malonate anion, generated from reaction of dimethyl malonate with sodium hydride in DMSO, in a DMSO solution at 80-150° C., preferably at 110° C., overnight gave dimethyl 2-(5-benzamido-4-benzyloxy-2-nitro)phenylmalonate in 36% yield. When dimethyl 2-(5-bybenzamido-4-benzyloxy-2-nitro)phenylmalonate was treated with NaOH in ethanol at 25-100° C., preferably refluxing, followed by acidification with HCl and mild heating at 25-100° C., preferably refluxing, provided the desired compound 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid in 93% yield. Treatment of 2-(5-amino-4-benzyloxy-2-nitro)phenylacetic acid at 0-50° C., preferably at 5° C. then gradual warming to room temperature, with borane in THF selectively reduced the carboxylic acid group to an alcohol, 2-(5-amino-4-benzyloxy-2-nitro)phenylethanol in 52% yield.