Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH:33]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:32][C:31]([CH2:43]Br)=[CH:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH:33]([CH2:34][OH:35])[CH2:32][C:31]([CH2:43][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:30]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CC(CO)C(CO)C2)c(=O)[nH]c1=O
Yield: 17.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (42 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]4[O:25][N:34]=[C:32]([C:31]5[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=5)[N:33]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) (196 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (97 mg, 38%). MS (ISP) 508.2 [(M+H)+]; mp 252° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:14]=[N:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][C:36]([CH3:38])=[O:37]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[C:36]([OH:37])([CH3:38])[CH3:35])[CH:14]=[N:13][CH:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1cncn1Cc1ccccc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)C(c1ccccc1C#N)n1cncc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
2-{5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-imidazol-1-ylmethyl}-benzonitrile (1.14 g, 3.34 mmol) is dissolved in THF (20 mL) and cooled to −78° C. LHMDS (1M in THF, 5 mL, 5 mmol) is added dropwise. Ten min after the end of addition, acetone (0.295 g, 5.01 mmol) is added. The reaction mixture is stirred at −78° C. for 40 min. It is then quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture is allowed to warm to room temperature, then poured into water. After extraction with ethyl acetate the organic phase is dried over Na2SO4 and concentrated in vacuo to give 2-(1-{5-[2-(tert-butyldimethylsilanyloxy)-ethyl]-imidazol-1-yl}-2-hydroxy-2-methyl-propyl)-benzonitrile; MS (ESI) m/z 400.3 (M+H)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(Cl)(Cl)Cl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=1)([O-:8])=[O:7]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
50 ml of chlorosulfonic acid were added within 30 minute dropwise to a solution of 13.7 g of p-nitrotoluene in 50 ml of chloroform under ice cooling. After the addition, the mixture was refluxed for 6 hours. After refluxing, the reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer was washed with water and dehydrated. Evaporation of chloroform gave 15.5 g of 5-nitro-2-methyl-phenylsulfonyl chloride of the m.p. 43°-44° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+]>CCO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-(3,3,3-trifluoropropoxy)pyridine-3-carboxylate (Intermediate 231, 0.240 g, 0.91 mmol) was dissolved in EtOH (7.5 mL) and 2M aq. sodium hydroxide (1.37 mL, 2.74 mmol) was added. The mixture was stirred at room temperature for 3 h. The mixture was then concentrated to a minimum volume and acidified by adding 2M hydrochloric acid.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7](CC)[CH:6]=1>C(OCC)C>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: CCc1cc(Br)ccc1N
Solvent: CCOCC
Product: N#CNc1ccc(Br)cc1
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-ethylaniline (20.6 g, 103 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere. The amine hydrobromide was filtered off, and the filtrate was concentrated in vacuo at room temperature and triturated with hexane to give 4-bromophenylcyanamide (2.3 g, 10%) as an off white solid. HRMS: calcd for C9H9BrN2+H+, 225.00218; found (ESI-FTMS, [M+H]+), 225.00277.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCNCC2)c2[nH]ncc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2[nH]ncc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole (24 mg, 0.065 mmol) and sodium cyanoborohydride (20.5 mg, 0.327 mmol) in acetonitrile (1.5 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added. The ice bath was removed and stirring continued for another 2 h. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2) to give 12.5 mg (50.2%) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 9.67 (bs, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.07 (m, 2H), 6.83 (s, 1H), 4.47 (q, J=10 Hz, 1H), 3.35 (d, J=10 Hz, 1H), 3.25 (d, J=10 Hz, 1H), 2.55-2.65 (m, 2H), 2.38 (s, 3H), 2.25-2.29 (m, 1H), 2.21(s, 3H), 1.9-2.2 (m, 5H), 1.40 (d, J=5.0 Hz, 3H); 13C-NMR (CDCl3, 126 MHz) δ 161.49 (d, J=980 Hz), 135.7, 133.9, 130.0, 128.8, 125.8, 125.7, 124.4, 118.9, 115.5, 115.3, 78.9, 51.9, 51.8, 50.9, 46.2, 32.7, 32.4, 22.4, 21.3; Mass spec.: 382.4 (MH)+.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(OCc2ccc(Br)cc2)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-5-methyl-pyridine (5.40 g, 19.4 mmol) described in Manufacturing Example 44-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 8.73 mL, 23.3 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (2.99 mL, 38.8 mmol) was then added dropwise thereto, which was stirred for 10 minutes at −78° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:6→1:4) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (2.90 g, 6.91 mmol) was dissolved in CH2Cl2 (10 ml). Trifluoroacetic acid (10 ml) was added and the mixture was stirred for 90 minutes at r.t. until analytical HPLC indicated complete consumption of the starting material. The solvent was evaporated, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=320.4 (M+H+), (1.73 g, 69%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH2:23]([NH2:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[O:29]1[C:30]2[CH:31]=[CH:32][C:24]([CH2:23][NH:33][C:4]([C:6]3[N:7]=[C:8]([C:15]4[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=4[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=3[OH:12])=[O:5])=[CH:25][C:26]=2[O:27][CH2:28]1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc2c(c1)OCO2
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc3c(c2)OCO3)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and piperonylamine (76 mg, 0.5 mmol). The title product was obtained as an off-white solid (18.6 mg, 45% yield). 1HNMR (500 MHz, CDCl3) δ: 12.35 (1H, s), 7.74 (1H, br s), 7.52–7.46 (1H, m), 7.04 (2H, dd, J=8.24, 7.33 Hz), 6.80 (1H, s), 6.78–6.74 (2H, m), 5.93 (2H, s), 4.48 (2H, d, J=6.10 Hz), 3.40 (3H, s). HRMS (ESI) calcd for C20H14F2N3O5 (M−H): 414.0902; found: 414.0900.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([O:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])(=[O:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:9]([O:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])([CH3:22])[CH3:21])(=[O:11])[CH3:10]
Reactant: CC(=O)OCCC(C)CCC=C(C)C
Reactant: Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(=O)OCCC(C)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
11.0 Parts of resorcinol, 10.0 parts of citronellyl acetate and 0.5 parts of p-toluene sulphonic acid are heated at 115° C. for 45 hours. The reaction mixture is then taken up in ether, washed with sodium bicarbonate solution, water, and evaporated. The residual oil is distilled and yields 3.9 parts of 7-(2',4'-dihydroxyphenyl)-3,7-dimethyloct-1-yl acetate b0.2 215° C. with the following percentage composition by weight:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][NH:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.[CH2:13]([O:20][CH2:21][N:22]1[C:30]2[C:29]([O:31][CH3:32])=[N:28][CH:27]=[N:26][C:25]=2[C:24]([CH:33]=O)=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:13]([O:20][CH2:21][N:22]1[C:30]2[C:29]([O:31][CH3:32])=[N:28][CH:27]=[N:26][C:25]=2[C:24]([CH2:33][N:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:9][CH2:10][OH:11])=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Reactant: CC1(C)OC[C@H](CNCCO)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ncnc2c(CN(CCO)C[C@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Yield: 79.9 %

Procedure:
The product from Example 14.1 (0.048 g, 0.274 mmol) was reductively aminated with 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.081 g, 0.274 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) in the same way as described for the R-enantiomer in Example 13.2. to give (S)-2-(((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)amino)ethanol (100 mg, 80%) as a colourless gum which slowly turned pale yellow. The 1H and 13C NMR were as described for the R-enantiomer in Example 13.2. +ESMS Found 457.2469 C24H33N4O5 (M+H)+ requires 457.2451.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][CH:17]=2)[CH:4]=[N:3][CH:2]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cncnc2)c1
Temperature: 25 °C
Yield: 31 %

Procedure:
5-pyrimidinyl-boronic acid (0.108 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.031 g in 31% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(Br)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
20 g of 3-bromo-2,6-difluorobenzaldehyde are dissolved in 450 ml of methanol and cooled in an ice bath; 3.42 g of sodium borohydride are then added portionwise thereto. The mixture is stirred at ambient temperature for 1 hour and then the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane and the organic phase is separated, dried and concentrated under reduced pressure. The residue is crystallised from n-pentane. 14.6 g of compound are obtained.
Reaction SMILES: [CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:16].[Cl-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]([NH2:6])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.0 g, 0.104 mol) in methylene chloride (30 ml) is added in a fine stream to concentrated sulfuric acid at room temperature. After stirring overnight at room temperature for 16 hours the mixture is poured onto ice, containing sodium chloride and ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate, brine and dried. Evaporation after washing with ether-pentane gives a solid (72%), mp 138.5°-140° C. Anal. calcd. for C10H14N2O3 : C, 57.13; H, 6.71; N, 13.33. Found: C, 56.89; H, 6.64; N, 13.16.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl[CH:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][C:41]2[CH:50]=[CH:51][CH:52]=[CH:53][C:40]1=2>ClCCl>[CH:53]1[C:40]2[CH:39]([N:3]3[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:5][CH2:4]3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH2:43][S:42][C:41]=2[CH:50]=[CH:51][CH:52]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Reactant: ClC1c2ccccc2CSc2ccccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C2c3ccccc3CSc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.02 g (21.5 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) are suspended in 100 ml abs. dichlormethane and added to 7.08 g (70.0 mmol) TEA. The mixture is cooled to ca 0° C. under moisture exclusion and a solution of 5.30 g (21.5 mmol) 11-chlor-6,11-dihydro-dibenzo[b,e]thiepine in 10 ml abs. dichlormethane is added dropwise. The mixture is stirred for 24 hours at RT without further cooling. Subsequently, the batch is washed with 50 ml 10% sodium hydroxide solution and 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The red brown residue is chromatographically purified three times over silica gel with CHCl3/CH3OH (100/0, 97/3 and 96/4 to 94/6). Subsequently, a further purification occurs by means of MPLC with CHCl3CH3OH (98/2). Yield: 0.5 g (5%) of a brittle, vitreous solid with a MP of 89–91° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=O)(C)(C)C>Cl.CO>[CH2:23]([C:9]1([C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[O:22])[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCC1(C(=O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCCC1(C(=O)c2ccc(Cl)c(Cl)c2)CCCN1
Yield: 67.9 %

Procedure:
A solution of 2-butyl-2-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.435 g, 1.09 mmol) in 1N HCl in MeOH (10.9 mL) was stirred at ambient temperature under nitrogen for 14 hours. The reaction mixture was concentrated in vacuo, then redissolved in DCM and concentrated in vacuo to remove excess HCl. Purification by chromatography (silica, 0-10% MeOH in DCM) gave (2-butyl-pyrrolidin-2-yl)-(3,4-dichloro-phenyl)-methanone (0.249 g, 0.740 mmol, 68%) as a white powder, MS=300 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].B>S(=O)(=O)(O)O.O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Agent: B
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(Sc2ccccc2O)c1

Procedure:
9-Cyano-6H-dibenz[b,e][1,4]thiepin (IIa) may be prepared according to the following general reaction scheme: ##STR6## wherein R2 anc R3 are as previously defined, by treating an appropriately substituted (R2 and/or R3) o-aminothiophenol with 2-chloro-4-nitrobenzoic acid in the presence of cuprous oxide to form the corresponding 2-(o-aminophenylthio)-4-nitrobenzoic acid which then is suspended in water, acidified with sulfuric acid, treated with sodium nitrite followed by sodium fluoroborate to obtain the diazonium fluoroborate which is heated in 50% sulfuric acid to obtain the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzoic acid. The acid product is treated with borane in tetrahydrofuran to form the corresponding 2-(o-hydroxyphenylthio)-4-nitrobenzyl alcohol which is cyclized in the presence of dicyclohexylcarbodiimide (DCC) to form the corresponding 9-nitro-6H-dibenz[b,e][1,4]oxathiepin. The nitro group then is reduced to the 9-amino compound with stannous chloride and the amine is treated with sodium nitrite followed by a mixture of cuprous cyanide and potassium cyanide to obtain the desired 9-cyano-6H-dibenz[b,e][1,4]oxathiepin of formula IIa.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-n2ccnc2)cc1
Product: O=S(=O)(Cl)c1ccc(-n2ccnc2)cc1

Procedure:
To chlorosulfonic acid cooled to 0° C. in an ice bath is added portionwise 1-phenyl-1H-imidazole. Monitor the progress of the reaction bythin-layer chromatography. When the reaction is complete, quench the mixture on ice. Saturated aqueous NaHCO3 is added until the solution is no longer acidic. Extract the mixture with CH2Cl2. Dry the organic layer over anhydrous Na2SO4 and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1>C1(C)C=CC=CC=1>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(Br)n1
Temperature: 120 °C
Reaction time: 13 h

Procedure:
In an argon atmosphere, sodium methoxide (1.82 g) was added to 2,6-dibromopyridine (8.0 g) in toluene (120 mL), followed by stirring at 120° C. for 13 hours. Subsequently, sodium methoxide (0.728 g) was added to the mixture, followed by stirring at 120° C. for 6 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound in an oily substance (5.64 g, 89%).