Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:32]3[CH2:33][CH2:34][CH:29]([C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 10 %

Procedure:
A mixture of 5.5 parts of 3-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, 3.6 parts of (4-fluorophenyl) (4-piperidinyl) methanone, 6 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the reaction mixtue is filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 0.6 parts (10%) of 5-chloro-1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazol-2-one; mp. 163.7° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>CO.[Pd]>[ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamide hydrochloride (0.38 g) in methanol (250 ml) was charged with a catalytic amount of 10% palladium on carbon (0.085 g). The reaction was placed under an atmosphere of hydrogen (50 psi; 3.44×105 Pa)) and shaken on a Parr apparatus for 2 hours. The reaction mixture was filtered and the solvent removed in vacuo. The solid product was recrystallized from 2-propanol to provide 0.34 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-amino-1-benzenesulfonamide hydrochloride as an off white powder, m.p. 203.1–205.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (very broad s, 2H), 8.21(d, J=8.0 Hz, 1H), 7.82 (m, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.13 (t, J=5.9 Hz, 1H), 6.60 (d, J=8.7 Hz, 2H), 5.92 (broad s, 2H), 4.55 (t, J=7.6 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.70 (q, J=6.4 Hz, 2H), 1.81 (m, 4H), 1.58–1.43 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3430, 3316, 3215, 3046, 2955, 2868, 2679, 1671, 1594, 1334, 1157, 1091, 851, 776, 759 cm−1; MS (EI) m/e 466.2145 (466.2151 calcd for C24H30N6O2S). Anal calcd for C24H30N6O2S*HCl: C, 57.30; H, 6.21; N, 16.71. Found: C, 57.36; H, 6.31; N, 16.21.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH3:29][NH:30][CH3:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:30]([CH3:31])[CH3:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CNC
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N,N,3-trimethylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and dimethylamine following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.32 (s, 1H), 8.04 (d, 1H), 7.66 (s, 1H), 7.31 (d, 1H), 7.06-7.18 (m, 3H), 3.08-3.19 (m, 4H), 2.96 (d, 3H), 2.54 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H). LRMS [M+H]=399.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][O:27][NH:28][CH3:29]>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:28]([O:27][CH3:26])[CH3:29])=[O:9]
Reactant: CNOC
Reactant: COc1ncc(F)cc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ncc(F)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.7 %

Procedure:
To a solution of 5-fluoro-2-methoxynicotinic acid (1 g, 5.8 mmol) in tetrahydrofuran (10 mL) was added 1,1′-carbonyldiimidazole (1.4 g, 8.77 mmol, 1.5 eq.) portionwise over a 5 min period. The resulting solution was stirred at room temperature for 20 min before adding O,N-Dimethyl-hydroxylamine hydrochloride (0.63 g, 6.43 mmol, 1.1 eq.) and then stirred for a further 72 hr. The resulting mixture was then partitioned between ethyl acetate (30 mL) and 2M aqueous hydrochloric acid (30 mL). The organic phase was washed with 1M aqueous sodium hydrogen carbonate (30 mL), followed by brine (30 mL) and then dried over magnesium sulphate. The resulting mixture was filtered and concentrated under reduced pressure to produce the title compound as a colourless oil (0.53 g, 43%). 1H NMR (400 MHz, CDCl3): δ ppm 3.36 (br. s., 3H) 3.55 (br. s., 3H) 3.97 (s, 3H) 7.33-7.44 (m, 1H) 8.06 (d, J=2.73 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20][Cl:21])[C:12]=2[N+:22]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C.[Pd]>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20][Cl:21])[C:12]=2[NH2:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Temperature: 60 °C

Procedure:
A mixture of 1-benzenesulfonylmethyl-3-(2-chloro-ethoxy)-5-fluoro-2-nitrobenzene (1.98 g, 5.3 mmoles) in ethanol (25 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.67 g, 4.87 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=1)=[O:12])[CH3:9].B([C:37]1[CH:42]=[CH:41][C:40]([C:43]2([C:46]([OH:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:22][C:23]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3([C:46]([OH:48])=[O:47])[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)=[CH:24][CH:25]=1)=[O:12])[CH3:9]
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Reactant: CC(OC(=O)Nc1ccncc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1)c1ccccc1Cl
Product: CC(OC(=O)Nc1ccncc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: trifluoro-methanesulfonic acid 4-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-pyridin-3-yl}-phenyl ester and 1-(4-boronophenyl)cyclopropanecarboxylic acid. After workup the crude material was purified via preparatory HPLC to give the title compound.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[F:12][C:13]1([F:24])[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([CH:22]=O)[C:15]=2[O:14]1.[NH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1>>[C:2]([C:3]1[CH:22]([C:21]2[C:15]3[O:14][C:13]([F:24])([F:12])[O:17][C:16]=3[CH:18]=[CH:19][CH:20]=2)[C:30]2[C:26](=[N:27][NH:28][CH:29]=2)[NH:25][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: O=Cc1cccc2c1OC(F)(F)O2
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2c1OC(F)(F)O2

Procedure:
The title compound was prepared from ethyl nipecotate, 2,2-difluoro-1,3-benzodioxol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.
Reaction SMILES: C1C2C(=O)NC3C=CC=CC=3SC=2C=CC=1.OCCOCC[C:23]1[C:33]2[S:32][N:31]=[CH:30][C:29]3[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=3[C:27]=2[C:26](N2CCCCC2)=[CH:25][CH:24]=1.P(Cl)(Cl)([Cl:46])=O>>[Cl:46][C:37]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:33]=3[S:32][N:31]=[CH:30][C:29]=2[CH:34]=[CH:35][CH:36]=1
Reactant: OCCOCCc1ccc(N2CCCCC2)c2c1SN=Cc1ccccc1-2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C1Nc2ccccc2Sc2ccccc21
Product: Clc1cccc2c1-c1ccccc1SN=C2

Procedure:
EP 0282236-A1 describes that a dibenzothiazepine derivative of the above-mentioned formula (5) can be processed to give 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-piperadinyldibenzothiazepine derivative which is of value as an antipsychotic pharmaceutical. In more detail, dibenzo-[b,f][1,4]thiazepin-11-one, which is a representative compound of the dibenzothiazepine derivatives of the formula (5), is reacted with phosphorus oxychloride to yield a 11-chloro-dibenzothiazepine derivative; and to the 11-chloro-dibenzothiazepine derivative is added piperazine to yield a 11-piperazinyl-dibenzothiazepine derivative, which is subsequently reacted with 2-chloroethoxyethanol under basic conditions to give the desired 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-piperadinyldibenzothiazepin.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=[O:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[C:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:17])(=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Cr](=O)(O)O
Reactant: O=C1CCc2c(Cc3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c1cccc2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 100 ml. of acetic acid is dissolved 11.1 g. of 4-benzyl indan-1-one, followed by the addition of 13.4 g. of chromic acid and 2.5 ml. of concentrated sulfuric acid. The mixture is stirred at room temperature for 2 hours, after which it is poured into 4 l. of water. After 200 g. of anhydrous potassium carbonate is added, the mixture is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel with chloroform as the eluent and, then, recrystallized from cyclohexane. The procedure gives 4-benzoylindan-1-one melting at 87°-89° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:19]3[CH:18]=[C:17]4[O:20][CH2:21][CH2:22][O:23][C:16]4=[CH:15][C:14]=3[N:13]([CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:12]2=[O:30])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[O:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[CH2:24][N:13]1[C:14]2[CH:15]=[C:16]3[O:23][CH2:22][CH2:21][O:20][C:17]3=[CH:18][C:19]=2[C:11]2([C:10]3=[CH:9][C:5]4[CH2:6][CH2:7][O:8][C:4]=4[CH:3]=[C:2]3[O:1][CH2:31]2)[C:12]1=[O:30]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C[C@H]1CCCO1)OCCO3
Product: O=C1N(C[C@H]2CCCO2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one was obtained (39%) as a colorless solid: mp 220-225° C.; 1H NMR (300 MHz, CDCl3) δ6.65 (s, 1H), 6.64-6.60 (m, 1H), 6.51-6.46 (m, 1H), 6.36 (s, 1H), 4.72 (dd, J=84.4, 8.9 Hz, 2H), 4.51 (dd, J=8.6, 8.6 Hz, 2H), 4.25-4.19 (m, 2H), 4.19-4.13 (m, 2H), 3.94-3.82 (m, 2H), 3.80-3.67 (m, 2H), 3.64-3.52 (m, 1H), 2.98 (t, J=8.6 Hz, 2H), 2.08-1.94 (m, 1H), 1.94-1.80 (m, 2H), 1.74-1.60 (m, 1H); MS (ES+) m/z 421.9 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)=[O:21])(=[O:3])[CH3:2].[K+].[Br-]>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccco2)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [Br-]
Agent: [K+]
Product: CC(=O)Nc1c(C(=O)c2ccco2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-(ethoxycarbonyl)-2-(2-furoyl)indole (step 2). m.p.: 227-228° C. 1H-NMR (CDCl3) δ: 10.72 (1 H, br s), 9.42 (1 H, br s), 8.42 (1 H, J=9.2 Hz), 7.78 (1 H, dd, J=0.7, 1.8 Hz), 7.47 (1 H, dd, J=0.7, 3.7 Hz), 7.37 (1 H, d, J=1.5 Hz), 7.08 (1 H, dd, J=1.8, 8.8 Hz), 6.71 (1 H,dd, J=1.6, 3.5 Hz), 2.32 (3 H, s) IR (KBr) ν: 3450, 1690, 1620, 1600, 1580, 1570, 1480, 1460, 1340, 1260, 1200, 900, 770, 630 cm−1
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14](OC)=[O:15])[CH2:3]1.[AlH](CC(C)C)CC(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC>[OH:15][CH2:14]/[CH:13]=[CH:12]/[C@@H:11]1[C@:18]2([CH3:26])[C@H:8]([C@H:7]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:25])[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][CH2:23]2)=[CH:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: COC(=O)/C=C/[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2/C=C/CO
Yield: 95.1 %

Procedure:
To a solution of 4.85 g of methyl (E)-3β-hydroxypregna-5,20-diene-21-carboxylate (Pouzar, V. et al., Collect. Czech. Chem. Commun, 1990, 55,1243), in 200 ml of anhydrous tetrahydrofurane, 81 ml of i-Bu2AlH (1M) in hexane were added dropwise in a nitrogen atmosphere at -78° C. After two hours the reaction mixture was treated with an aqueous solution of citric acid (30 g in 100 ml of water). The mixture was filtered on Celite and the residue washed with ethyl acetate. The organic solution was dehydrated over anhydrous sodium sulfate and evaporated to dryness under vacuum, to give 4.25 g of (E)-21-hydroxymethylpregna-5,20-dien-3β-ol as a white solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[F:51])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=3)=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 55.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(2-fluorobenzyl)-1-piperidinecarboxamide (0.21 g, 0.27 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:35]=[C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:38]=[CH:39][CH:40]=2)[CH2:31][CH2:32]1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(CN2CCOCC2)c1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36](=[O:39])[NH:37][CH3:38])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CNC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: CNC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Yield: 75.4 %

Procedure:
The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan- 2-yl)-1α, 2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-ol (yield: 76%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH2:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].B#B.[Br:13]Br.C[O-].[Na+]>O1CCCC1.CO>[Br:13][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: C=Cc1cccc(CC)c1
Reactant: BrBr
Agent: B#B
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(CCBr)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 3-ethyl-1-vinylbenzene (Preparation 20, 1.45 g, 10.9 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen at 0° C. was added diborane (1.0M solution in tetrahydrofuran, 4 ml, 4 mmol) dropwise over 30 min. After 30 min at room temperature, methanol (0.1 ml) was added to destroy excess diborane. The reaction mixture was cooled to 0° C., and bromine (0.59 ml, 11 mmol) and a solution of sodium methoxide in methanol (12.1 mmol) were added via separate syringes at such a rate that a pale yellow coloration was always maintained. The reaction mixture was partitioned between aqueous saturated potassium carbonate solution and hexane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica column chromatography eluting with hexane to afford the title compound (640 mg, 28%).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:29])([C:26](=[O:28])[CH3:27])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:14])[C:26](=[O:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Yield: 55.5 %

Procedure:
29.7 g (0.55 mol) of sodium methylate were dissolved in 500 ml of methanol and 70.4 g (0.55 mol) of 4-chlorophenol were added to the solution, whilst stirring. After the mixture had been stirred for 10 minutes, the solvent was distilled off under reduced pressure and the residue was taken up in 100 ml of glycol. This solution was added to a solution of 135 g (0.5 mol) of 2,2-dimethyl-1-tosyloxy-butan-3-one in 200 ml of glycol. The reaction mixture was stirred for 48 hours at 100° to 120° C., and was cooled and stirred into 2,000 ml of water. The mixture was extracted with twice 250 ml of diethyl ether, and the combined organic phases were washed with three times 100 ml of water, once with 100 ml of 10% strength sodium hydroxide solution and again with 100 ml of water, dried over sodium sulphate and distilled. 62.9 g (55.7% of theory) of 1-(4-chlorophenoxy)-2,2-dimethylbutan-3-one of boiling point 135°-140° C./0.4 mm Hg were obtained. ##STR10##
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:13]
Reactant: Cc1c(OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1OC(C)(C)C
Yield: 98 %

Procedure:
To a solution of 2-methyl-3-tert-butoxynitrobenzene K3 (1.31 g; 6.26 mmol) in absolute ethanol (30 mL) was added 10% Pd/C catalyst (130 mg). The solution was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 63 h. The reaction mixture was filtered through a Celite pad, rinsed with absolute EtOH and evaporated to dryness to provide 2-methyl-3-tert-butoxyaniline K4 (1.1 g; 6.14 mmol; 98% yield). M.S. 180 (M+H)+. Homogeneity by HPLC (TFA) @220 nm: 96%
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>O1CCCC1.O.Cl>[Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of methyl 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate (0.314 g, 0.973 mmol) in tetrahydrofuran (15 mL) and water (10 mL) was added lithium hydroxide (0.148 g, 6.18 mmol). The mixture was heated to reflux for 1.5 hours, cooled to ambient temperature. The reaction was diluted with 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography, with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% to afford the title compound as a colorless solid (0.25 g, 83%): 1H NMR (300 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1H), 6.70 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 2.52-1.90 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −92.3 (d, J=238 Hz, 1F), −102.6 (d, J=238 Hz, 1F), −105.3 (s, 1F); MS (ES−) m/z 307.2, 309.2 (M−1).