Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:9]2=[O:11]
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(=O)CC(c1ccccc1)O2
Yield: 34 %

Procedure:
A mixture of 1-(2-hydroxy-5-methyl-phenyl)-ethanone (15 g, 0.10 mol), benzaldehyde (10.6 g, 0.10 mol) and borax (38 g, 0.10 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-methyl-2-phenyl-chroman-4-one (8.1 g, 34%). 1H-NMR (CDCl3): 2.32 (s, 3H), 2.86 (d, 1H), 3.06 (t, 1H), 5.44 (d, 1H), 6.96 (d, 1H), 7.38 (d, 1H), 7.44 (m, 5H), 7.71 (s, 1H).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc(CO)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2cc(CO)cnc2C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 5 ml. of anhydrous pyridine was added 0.86 g. of p-anisoyl chloride dropwise under cooling. After standing overnight the resulting mixture was poured into ice water and extracted with chloroform.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]([OH:30])([C:21]3N=C(C(F)(F)F)S[CH:25]=3)[CH2:16]2)[CH3:14])=[CH:8][CH:7]=1)([OH:3])=[O:2].C(CO[C:37]1[CH:42]=[CH:41]C(CC(N2CCOC(O)(C3N=C(C(F)(F)F)SC=3)C2)C)=[CH:39][CH:38]=1)(OC)=O>>[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([N:15]2[CH2:20][CH2:19][O:18][C:17]([OH:30])([C:21]3[CH:39]=[CH:38][CH:37]=[C:42]([CH3:41])[CH:25]=3)[CH2:16]2)[CH3:14])=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(O)(c2csc(C(F)(F)F)n2)C1
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3csc(C(F)(F)F)n3)C2)cc1
Product: Cc1cccc(C2(O)CN(C(C)Cc3ccc(OCC(=O)O)cc3)CCO2)c1

Procedure:
N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine.
Reaction SMILES: [C:1]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[C:11]2[O:16]C(C)(C)[O:18][CH2:19][C:10]=12)([O:3][CH2:4][CH3:5])=[O:2].[ClH:22].C(=O)(O)[O-].[Na+]>O>[ClH:22].[CH3:15][C:12]1[C:11]([OH:16])=[C:10]([CH2:19][OH:18])[C:9]([CH2:8][S:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:14][N:13]=1
Reactant: CCOC(=O)CSCc1cnc(C)c2c1COC(C)(C)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CSCc1cnc(C)c(O)c1CO
Temperature: 0 °C

Procedure:
A mixture of 1.0 g. of the compound from Step A, 6.0 ml. of 2.5 N hydrochloric acid and 10 ml. of water is heated at 50°C. for 45 minutes. The mixture is made alkaline with solid sodium bicarbonate and concentrated to dryness. The residue is extracted with 50 ml. of hot isopropanol. The extract is cooled to 0°C., saturated with dry hydrogen chloride and concentrated to dryness. The solid residue is isolated by trituration with ether and filtration and dried to give 2-methyl-3-hydroxy-4-hydroxymethyl-5-ethoxycarbonylmethylthiomethylpyridine hydrochloride.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC(=O)OCC)n1ccc2cc(N)ccc21
Yield: 78.1 %

Procedure:
A mixture of 3-(5-nitro-indol-1-yl)-hexanoic acid ethyl ester (1.49 g, 4.9 mmol), and 10% palladium on activated carbon (149 mg) in ethanol (15 mL) was hydrogenated in a hydrogen balloon for 2 days. The mixture was filtered through Celite, and the Celite was washed with methanol. The filtrate and washing were combined, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (20, 30%) to afford the title compound (1.05 g, 78% yield) as dark brown oil. 1H NMR (CDCl3) δ 7.22 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=3.2 Hz), 6.90 (d, 1H, J=2.3 Hz), 6.66 (dd, 1H, J=2.2, 8.7 Hz), 6.33 (d, 1H, J=3.2 Hz), 4.78–4.73 (m, 1H), 4.02–3.96 (m, 2H), 3.47 (bs, 2H), 2.87–2.74 (m, 2H), 1.94–1.87 (m, 1H), 1.84–1.77 (m, 1H), 1.27–1.09 (m, 2H), 1.08 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].[C:27]([C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31])([OH:29])=[O:28].C(N1C[C@H]2[C@H](CCCN2)C1)C1C=CC=CC=1.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.C(N1C[C@@H]2[C@@H](CCCN2)C1)C1C=CC=CC=1>CN(C)C=O>[C:22]([C@H:20]([C@@H:18]([C:17]([OH:26])=[O:25])[OH:19])[OH:21])([OH:24])=[O:23].[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:34]([OH:36])(=[O:35])[C@H:32]([C@@H:30]([C:27]([OH:29])=[O:28])[OH:31])[OH:33]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Agent: c1ccc(CN2C[C@H]3CCCN[C@H]3C2)cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 18 °C

Procedure:
73.6 g (0.34 mol) of cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane dissolved in 111 ml of dimethylformamide is added a drop at a time to a solution of 102.9 g (0.685 mol) of L(+)-tartaric acid in 343 ml of dimethylformamide. The batch is seeded with [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate and gradually cooled to an interior temperature of 18° C. The crystals are suctioned off and the filtrate seeded with [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]-nonane L-tartrate and agitated until it crystallizes completely. ([S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate can be obtained from the mother liquor subsequent to concentration and release of the base by purification with D(-)-tartaric acid as described for Method I.) The product is suctioned off, washed with dimethylformamide and isopropyl alcohol, and dried in the air. The crystals are recrystallized from 88% ethanol. 52 g of [S,S]-8-benzyl-2,8-diazabicyclo[4.3-O]nonane L-tartrate trihydrate are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH2:19][Cl:20])=[C:13]([OH:22])[CH:12]=1)(=[O:9])[CH3:8]>C(OCC)(=O)C.O>[Cl-:20].[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH2:19][N:4]2[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]2)=[O:21])=[C:13]([OH:22])[CH:12]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(NC(=O)CCl)c(O)c1
Reactant: Cn1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NC(=O)Cn2cc[n+](C)c2)c(O)c1
Product: [Cl-]
Yield: 79.6 %

Procedure:
9.85 ml of N-methylimidazole (123 mmol) were added to a suspension of 10 g (41 mmol) of N-(4-acetylamino-2-hydroxyphenyl)-2-chloroacetamide obtained above in the preceding step in 30 ml of ethyl acetate. The reaction medium was heated under reflux for 6 hours and then the insoluble product formed was drained and abundantly washed with ethyl acetate. The brown solid thus obtained was taken up in water and filtered and then the filtrate was poured over dioxane. The precipitate obtained was drained, abundantly washed with dioxane and then with isopropyl ether and dried under vacuum to give 10.6 g of 3-[(4-acetylamino-2-hydroxyphenylcarbamoyl)methyl]-1-methyl-3H-imidazol-1-ium chloride in the form of a purple-brown powder whose melting point was 225° C., (yield 79%).
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1)#N.O>C1COCC1>[CH3:37][N:29]([CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:15]([C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)=[CH:24][CH:25]=1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: CN1CCC(N(C)C(=O)c2ccc(C#N)cc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of N,N-diethyl-2,3-dimethyl-benzamide (578 mg, 2.82 mmol) in anhydrous THF (3 mL) under N2 at −78° C. was added dropwise n-BuLi (2.5M in n-hexanes, 2.4 mL, 5.92 mmol) to give a deep red solution. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was transferred dropwise, via syringe, to a reaction vessel containing 4-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (725 mg, 2.82 mmol) in anhydrous THF (5 mL) at −78° C. and under N2. The reaction mixture was stirred at −78° C. for 3.5 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL). The combined organic layers concentrated in vacuo and the resultant solid was triturated with 2:1 isohexane/EtOAc, filtered and dried in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 15% MeOH/CH2Cl2 to afford N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (487 mg, 44%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:21])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[CH:22]([C:24]1[CH:25]=C(C=C[CH:36]=1)OCCCC(O)=O)=O.CN1CCNCC1.CN(C)CCCN=C=NCC.O.O[N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=N1>ClCCl.O>[C:24]([C:63]1[CH:64]=[CH:65][C:60]2[NH:59][C:16]([C:15]3[CH:14]=[C:13]([CH:20]=[CH:19][CH:18]=3)[O:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:21])=[N:57][C:61]=2[CH:62]=1)([CH3:25])([CH3:36])[CH3:22]
Reactant: O=Cc1cccc(OCCCC(=O)O)c1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(C(=O)CCCOc2cccc(C=O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)CCCOc2cccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-[4-(4-Methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde. To a solution of 4-(3-formyl-phenoxy)-butyric acid (981 mg, 4.72 mmol, 1.0 equiv) and N-methylpiperazine (576 mg, 5.19 mmol, 1.1 equiv) in dichloromethane at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI; 1.18 g, 6.14 mmol, 1.3 equiv) and 1-hydroxybenzotriazole hydrate (HOBT; 701 mg, 5.19 mmol, 1.1 equiv). The reaction mixture, which was allowed to warm to rt, was stirred for 2.0 h and then poured into water. This mixture was extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 5% MeOH in dichloromethane) to afford 847 mg (62%) of the desired product. 1H NMR (400 MHz, CD3OD): 9.72 (s, 1H), 7.29-7.23 (m, 2H), 7.22-7.19 (m, 1H), 7.05-6.98 (m, 1H), 3.87 (t, J=6.1 Hz, 2H), 3.43-3.31 (m, 4H), 2.39 (t, J=7.2 Hz, 2H), 2.27-2.17 (m, 4H), 2.08 (s, 3H), 1.92-1.80 (m, 2H). B. 4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin-1-yl)-butan-1-one. This compound was prepared by the method described in General Procedure 3 using 3-[4-(4-methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde (81.2 mg, 0.28 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (46 mg, 0.28 mmol, 1.0 equiv), and Na2S2O5 (69 mg, 0.36 mmol, 1.3 equiv). Purification by Method 2 afforded 77 mg (64%) of the title compound. MS (electrospray): mass calculated for C26H34N4O2, 434.27; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.69-7.62 (m, 3H), 7.54 (d, J=8.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.06 (dd, J=8.2, 2.2 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 3.70-3.50 (m, 4H), 2.62 (t, J=7.3 Hz, 2H), 2.49-2.40 (m, 4H), 2.32 (s, 3H), 2.16-2.09 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.C([CH2:14][C:15]([OH:17])=[O:16])#N.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1Cc2ccccc2C1=O
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1=C(CC(=O)O)c2ccccc2C1
Reaction time: 21 h

Procedure:
2-Methylindanone (0.112 mole), cyanacetic acid (10.5 g., 0.123 mole), acetic acid (6.6 g.), and ammonium acetate (1.7 g.) in dry toluene (15.5 ml.) was refluxed with stirring for 21 hrs., as the liberated water was collected in a Dean Stark trap. The toluene was concentrated and the residue dissolved in 60 ml. of hot ethanol and 14 ml. of 2.2 N aqueous potassium hydroxide solution. 22 g. Of 85% KOH in 150 ml. of water was added and the mixture refluxed for 13 hr. under N2. The ethanol was removed under vacuum, 500 ml. water added, the aqueous solution washed well with ether and then boiled with charcoal. The aqueous filtrate was acidified to pH 2 with 50% hydrochloric acid, cooled and the precipitate of 2-methylinden-3-acetic acid was collected.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1.C([Si]([O:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]2[CH2:68][O:67]2)=[CH:60][CH:59]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:34]([NH:33][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:68][C@H:66]([OH:67])[CH2:65][O:64][C:61]4[CH:62]=[CH:63][C:58]([OH:57])=[CH:59][CH:60]=4)=[CH:8][CH:9]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:29][CH:28]=1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCN)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(CCc2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 35.5 %

Procedure:
N-[4-(2-{3-[4-(2-Aminoethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}ethyl)phenyl]-N′-hexylurea formate (0.541 g, 1.03 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.250 g, 0.619 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.195 g, 0.220 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)([O-])=O.[S].Cl[C:13]1[CH:19]=CC(N)=CC=1.[C:20]([O-:23])(=[O:22])C.[K+]>[Se].C(NCCCC)CCC.C(O)C>[CH2:19]([O:23][C:20](=[O:22])[NH:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)[CH3:13]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Agent: [S]
Agent: [Se]
Solvent: CCO
Solvent: CCCCNCCCC
Product: CCOC(=O)Nc1ccc(Cl)cc1
Yield: 510.4 %

Procedure:
26.6 g of 4-nitrochlorobenzene, 2.0 g of sulphur, 0.2 g of metallic selenium, 4.4 g of 4-chloroaniline, 2.36 g of potassium acetate, 3 g of the metal oxide mixture used in Example 1, 1.28 g of di-n-butylamine and 169 g of absolute ethanol were reacted together at 180° C. as described in Example 1. The reaction mixture was worked up as described in Example 1 and yielded 24.5 g of ethyl-N-(4-chlorophenyl)-carbamate, b.p. 118°-120° C./0.2 mm. The substance was 98.5% pure according to gas chromatographic analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[S:9][C:10]([C:12](OCC)=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:21]=1.[NH3:23]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[S:9][C:10]([C:12]([NH2:23])=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: N
Reactant: CCOC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 45 °C
Yield: 100 %

Procedure:
A pressure tube containing a solution of ethyl 9-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxylate (32 mg, 0.08 mmol) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 45° C. for two weeks. Evaporation of the reaction mixture furnished the title compound (31 mg, 0.08 mmol, 100%) as a pale brown solid: 1H NMR (500 MHz, d4-methanol) delta 1.61-1.68 (m, 2H), 2.93-3.02 (m, 2H), 3.59 (td, J=7.33, 4.26 Hz, 1H), 3.67 (td, J=8.04, 3.78 Hz, 1H), 7.05 (d, J=9.46 Hz, 1H), 8.18 (d, J=6.94 Hz, 1H), 8.39 (s, 1H); M+1=352/354.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9]C=2C#N)([CH3:4])([CH3:3])[CH3:2].[OH-:19].[K+].[CH3:21][CH2:22][OH:23]>>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:21]=2[C:22]([OH:19])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C#N)c2[nH]1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)O)c2[nH]1
Yield: 77 %

Procedure:
2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile (4.6 g, 19 mmol) was added to a solution of KOH in EtOH (10%, 100 mL) and the mixture was heated at reflux overnight. The solution was evaporated to remove alcohol, a small amount of water was added, and then the mixture was acidified with dilute hydrochloric acid. Upon standing in the refrigerator, an orange-yellow solid precipitated, which was purified by chromatography on silica gel (15% EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 10.79 (brs, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 6.57 (s, 1H), 1.39 (s, 9H).
Reaction SMILES: [N+](C1SC(S([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]3[CH:40]4[CH2:41][CH:42]([OH:44])[CH2:43][CH:36]3[CH2:37][O:38][CH2:39]4)[CH2:13]2)(=O)=O)=CC=1)([O-])=O.[N+](C1SC(S([N:56]2[CH2:61][CH2:60][N:59]([C:62]3[N:67]=[CH:66][C:65]([C:68]([OH:77])([C:73]([F:76])([F:75])[F:74])[C:69]([F:72])([F:71])[F:70])=[CH:64][N:63]=3)[C@@H:58]([CH2:78][N:79]3[CH:84]4[CH2:85][C:86](=[O:88])[CH2:87][CH:80]3[CH2:81][O:82][CH2:83]4)[CH2:57]2)(=O)=O)=CC=1)([O-])=O.[OH-].[K+].CO>O>[F:32][C:29]([F:30])([F:31])[C:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C@@H:14]2[CH2:34][N:35]2[CH:36]3[CH2:43][CH:42]([OH:44])[CH2:41][CH:40]2[CH2:39][O:38][CH2:37]3)=[N:23][CH:22]=1)([OH:33])[C:25]([F:26])([F:27])[F:28].[F:76][C:73]([F:74])([F:75])[C:68]([C:65]1[CH:64]=[N:63][C:62]([N:59]2[CH2:60][CH2:61][NH:56][CH2:57][C@@H:58]2[CH2:78][N:79]2[CH:80]3[CH2:87][C:86](=[O:88])[CH2:85][CH:84]2[CH2:83][O:82][CH2:81]3)=[N:67][CH:66]=1)([OH:77])[C:69]([F:70])([F:72])[F:71]
Reactant: O=C1CC2COCC(C1)N2C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CN3C4COCC3CC(O)C4)C2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CC2COCC(C1)N2C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Product: OC1CC2COCC(C1)N2C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 25-mL round-bottomed flask was charged with a 1:1 mixture of 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (300 mg, 0.44 mmol, Example 98, Step 5), potassium hydroxide (749 mg, 13.34 mmol), MeOH (5 mL) and water (2 mL) and was stirred at room temperature for 30 min. The solvent was removed in vacuo and then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layers were dried (Na2SO4), filtered, and concentrated to give 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (215 mg) which were used without purification.
Reaction SMILES: C([Mg]Br)C.CCOCC.[C:10]([CH:12]1[CH2:14][CH2:13]1)#[CH:11].[Si:15]([O:22][CH2:23]/[CH:24]=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1.C(Cl)Cl>[Si:15]([O:22][CH2:23][C@@H:24]([NH:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:11]#[C:10][CH:12]1[CH2:14][CH2:13]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](C#CC1CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C

Procedure:
3.0 M ethyl magnesium bromide in Et2O (0.360 mL, 1.081 mmol) was added to a solution of ethynylcyclopropane (71.5 mg, 1.081 mmol) in THF (4 mL). The solution was heated to 50° C. for 1 h, then the resulting Grignard was added to a −78° C. solution of (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (100 mg, 0.360 mmol) in DCM (4.00 mL), and the reaction was allowed to warm to room temperature. After 3h, the reaction was quenched with sat. aq. NH4Cl. The layers were separated and the organics were dried over magnesium sulfate and concentrated to provide (S)—N—((S)-1-((tert-butyldimethylsilyl)oxy)-4-cyclopropylbut-3-yn-2-yl)-2-methylpropane-2-sulfinamide, which was used directly. LCMS (m/z): 344.1 (MH+), 1.23 min.