Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH3:38])[CH3:29])=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Br)cc3)nc3cccnc32)cc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g, 0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) suspension of N,N-dimethyl-p-phenylenediamine dihydrochloride (4.04 g, 0.0193 mole), triethylamine (8.2 g, 0.081 mole), and anhydrous dimethylformamide (100 ml). The reaction mixture was stirred overnight at room temperature, filtered, and poured into ice water (500 ml). The mixture was allowed to precipitate, and filtered. The filter cake was triturated in potassium bicarbonate solution (100 ml), filtered, and rinsed with water (100 ml). The cake was twice recrystallized from tetrahydrofuran/ethyl alcohol, giving 2.8 g (31%) of a white solid, mp 248°- 250° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N12CCCC=C1CCNC[CH2:14]2.S(OC)(OC)(=O)=O.Cl>C(#N)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: C1=C2CCNCCN2CCC1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 2-amino-5-chloro-3-methylbenzoic acid (i.e. the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5° C. was added 1,4-diaza-bicyclo[5.4.0]undec-7-ene (DBU, 90 mL, 92 g, 600 mmol), and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5° C. After stirring 3 h at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 3 h at this temperature, more additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 2 h at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10° C. The resulting suspension was stirred for 30 minutes at 0-5° C., then filtered, and the solids were washed with ice-cold 2:1 water-acetonitrile (3×100 mL), and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added, and the mixture was stirred at room temperature for 1 h. Then the solids were filtered, washed with 4:1 water-methanol (100 mL), then with water (3×100 mL), and dried under nitrogen to afford the title compound as a low-melting white solid, 87.6 g (87.8% yield). HPLC of the solid product showed 99.7 area % of the title ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21]C(C)(C)C)=[O:20])[C:13](=[O:29])[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:11]([CH3:40])=[C:10]2[C:41]([C:43]2[O:44][CH:45]=[CH:46][CH:47]=2)=[O:42])=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([OH:21])=[O:20])[C:13](=[O:29])[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:11]([CH3:40])=[C:10]2[C:41]([C:43]2[O:44][CH:45]=[CH:46][CH:47]=2)=[O:42])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(Cc2cccc(C(=O)OC(C)(C)C)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(Cc2cccc(C(=O)O)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
tert-Butyl 3-{[6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}benzoate (Example 43) (50 mg, 0.078 mmol) is dissolved in trifluoroacetic acid (2 ml). After 15 minutes stirring, the solution is concentrated in vacuo and the residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:10]1[C:4]2[C:3]3[C:11](=[O:12])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][C:2]=3[S:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccccc1O)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Temperature: 140 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of 2-bromo-4,5,6,7-tetrahydro-N-(2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide (5.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (4.2 g) and the mixture was stirred at 140° C. for 4 hours. The completion of the reaction was confirmed by thin layer chromatography. The mixture was cooled to room temperature and the reaction mixture was poured into water (300 ml). After neutraition with hydrochloric acid, the mixture was extracted twice with chloroform and washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[OH:23].C(=O)([O-])[O-].[K+].[K+].C[N:31](C)C=O.C1(C)C=C(C)C=C(C)C=1S(NO)(=O)=O>C(Cl)Cl>[NH2:31][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2c(COC(C)=O)c(F)c(F)cc2c1O
Agent: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(N)c2c(COC(C)=O)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
10.7 g (32.9 mmol) of ethyl 6,7-difluoro-4-hydroxy-8-acetoxymethylquinoline-3-carboxylate and 14.2 g (65.8 mmol) of anhydrous potassium carbonate were added to 130 ml of N,N-dimethylformamide, and the solution was stirred at room temperature for 4 hours. 14 g (NET 8.97 g, 49 mmol) of mesitylenesulfonylhydroxyamine was dissolved in 100 ml of methylene chloride, and after drying over sodium sulfate, while cooling on ice, this solution was dropped to the previous solution through 20 minutes. Then, the obtained solution was left overnight as it was. To this solution, 100 ml of water was added, and the solution was stirred at room temperature for 1 hour. The solution was extracted with methylene chloride, and the organic layer was washed. After drying over sodium sulfate, the solvent was removed under reduced pressure and ether was added to the crystal residue. The crystals were filtered off and washed with ether to obtain 6.4 g of the subject compound (97) in a 57% yield. The results of the analysis of this compound were as follows:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9]C(C)C)=[O:8])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccccc1OC(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 17.6 %

Procedure:
To a stirred solution of Isopropyl 2-isopropoxy-benzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Isopropoxy-benzoic Acid (7.6 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14](=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[CH:8]2)=[O:4].Br[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1)=[O:29].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:27][C:28](=[O:29])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1)[C:9]([C:14](=[O:25])[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]1)=[CH:8]2)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 3 g 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid methyl ester in 80 ml absolute DMF 419 mg NaH (60% in mineral oil) were added under an argon atmosphere. After stirring for 30 min. 2.179 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the reaction mixture stirred for 2 h at RT. Then additional 105 mg NaH (60% in mineral oil) and 1.089 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 1 h at RT. The solvent was removed in vacuo and the residue purified by chromatography on silica gel using CH2Cl2/MeOH/HOAC/H2O=9/1/0.1/0.1. The fractions containing the product were concentrated and lyophilized in a water/CH3CN mixture. Yield: 3.68 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1>>[S:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:12]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: c1cc2cc(-c3ccsc3)ccc2[nH]1

Procedure:
The title compound was prepared as in (D29) from 5-bromoindole and thiophene-3-boronic acid to give (D40) (1.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]#[N:25])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][OH:27]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24](=[NH:25])[NH:26][OH:27])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC#N
Solvent: CCO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC(=N)NO
Yield: 90.4 %

Procedure:
To a suspension of {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile (14.7 g; 39.3 mmol) in EtOH (600 ml) was added a 50% aqueous solution of NH2OH (24.1 ml; 393 mmol) and the reaction mixture was refluxed for 2 hours. The solvent was evaporated off and the residue was triturated with ether, collected by filtration and dried under vacuum to give 2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-N-hydroxyethanimidamide (14.5 g; 90% yield). 1H NMR (400 MHz; DMSO-d6): 3.98 (s, 3H), 4.58 (s, 2H), 5.70 (s, 2H), 7.38 (s, 1H), 7.65 (d, 1H), 7.84 (s, 1H), 7.89 (dd, 1H), 8.26 (d, 1H), 8.55 (s, 1H), 9.41 (s, 1H), 9.64 (s, 1H); MS (EI) for C17H15Cl2N5O3: 408.05 (MH+).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH2:14](O)[CH3:15]>>[CH2:14]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])[CH3:15]
Reactant: CCO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1CCC(=O)N1
Reaction time: 15 h
Yield: 99 %

Procedure:
A suspension of 30.0 g of L-pyroglutamic acid 133 (232 mmol) in 100 ml of anhydrous ethanol was slowly added with 20 ml of SOCl2 (274 mmol, 1.2 eq.) at 0° C. and subsequently stirred for 15 h, and the batch was thawed to room temperature to form a clear solution. For work-up, all volatile components were completely removed under vacuum, the remaining residue was subsequently taken up in 500 ml of ethyl acetate and successively stirred over K2CO3 and MgSO4, each time removing the drying agent by suction. Filtration over a small amount of silica gel and solvent removal under vacuum afforded 36.0 g (230 mmol, 99%) of ester 203 in the form of a slightly yellowish, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C)[CH:18]=3)[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC(=O)CN1C2C(=CC(C)=CC=2)C(S(C2C=CC([Cl:50])=CC=2)(=O)=O)=C1C)C>>[Cl:50][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]([CH3:25])=[C:11]2[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reactant: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2cccc(Cl)c2n1CC(=O)O

Procedure:
The title compound was prepared by the method of example 2 part (d) using the product from part (c).
Reaction SMILES: [OH-:1].[Na+].OO.[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([S:12][C:13]2[CH:20]=[C:19]([N:21]3[C:25]4=[N:26][CH:27]=[CH:28][C:29]([C:30]5[CH:31]=[N:32][C:33]6[C:38]([CH:39]=5)=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:24]4[C:23]([CH3:40])=[CH:22]3)[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[CH2:8][CH2:7]1.O>CS(C)=O.C(O)C>[OH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([S:12][C:13]2[CH:20]=[C:19]([N:21]3[C:25]4=[N:26][CH:27]=[CH:28][C:29]([C:30]5[CH:31]=[N:32][C:33]6[C:38]([CH:39]=5)=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:24]4[C:23]([CH3:40])=[CH:22]3)[CH:18]=[CH:17][C:14]=2[C:15]([NH2:16])=[O:1])[CH2:8][CH2:7]1
Reactant: Cc1cn(-c2ccc(C#N)c(S[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(C(N)=O)c(S[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reaction time: 0.5 h

Procedure:
Trans-4-mercaptocyclohexanol (0.050 g), tris(dibenzylideneacetone)dipalladium(0) (0.008 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.010 g), and N,N-diisopropylethylamine (0.116 mL) were added to a solution of (40f) (0.150 g) prepared in Example 40(6) in 1,4-dioxane (1.71 mL), followed by stirring under nitrogen flow at 120° C. for 6 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain a crude product of 2-(trans-4-hydroxycyclohexylthio)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile. Subsequently, an aqueous sodium hydroxide solution (4 M, 0.851 mL) and a 30% hydrogen peroxide solution (0.193 mL) were added to a solution of this 2-(trans-4-hydroxycyclohexylthio)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile in DMSO (0.4 mL) and ethanol (1.6 mL) at room temperature, followed by stirring for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed by sprinkling water and ether, and then dried under reduced pressure to obtain (67) (0.023 g, the second stage yield: 13%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[C:21]([F:22])=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=3[F:23])=[CH:12][C:4]=2[O:3]1.[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[K+]>ClCCCl>[F:22][C:21]1[CH:20]=[C:17]([CH2:18][NH:29][CH2:28][CH2:27][CH:26]([CH3:30])[CH3:25])[CH:16]=[C:15]([F:23])[C:14]=1[O:13][C:11]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:24])([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: CC1(C)OC(=O)c2ccc(Oc3c(F)cc(C=O)cc3F)cc2O1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCNCc1cc(F)c(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3,5-difluoro-benzaldehyde (I-1b-2: 1.0 g) and 3-methyl-butylamine (0.31 g) were combined in 1,2-dichloroethane (25 mL). After stirring at ambient temperature for 1 hour, sodium triacetoxyborohydride (3.3 g) was added to the solution. After stirring overnight, the reaction mixture was treated with an aqueous 2 N potassium hydroxide solution, the organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to provide the title compound (I-1c-3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH3:34]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CNCCO
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 495 (MH+).
Reaction SMILES: [C:1]1([CH2:11][C:12]2[C:13]([NH2:18])=[N:14][NH:15][C:16]=2[NH2:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:19](OC)(=[O:25])[CH2:20][C:21](OC)=[O:22].C[O-].[Na+]>CO>[NH2:18][C:13]1[C:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[C:16]2[NH:17][C:19](=[O:25])[CH2:20][C:21](=[O:22])[N:15]2[N:14]=1
Reactant: Nc1n[nH]c(N)c1Cc1cccc2ccccc12
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nn2c(c1Cc1cccc3ccccc13)NC(=O)CC2=O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1-naphthalenylmethyl)-1H-pyrazole-3,5-diamine (2.18 g, 9.15 mmol), dimethyl propanedioate (3.63 g, 27.4 mmol) in Methanol (30 mL) was added sodium methoxide (1.68 g, 31.1 mmol). The reaction mixture was stirred at 65° C. for 18 h. After the reaction mixture was cooled down, the solvent was evaporated. Water (10 mL) was added in. The solid precipitated. The mixture was neutralized with 1 N HCl. The precipitated product was filtered and dried in vacuo (2.7 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.65 (s, 2H) 4.21 (s, 2H) 5.59 (br. s., 2H) 7.08 (d, J=6.82 Hz, 1H) 7.27-7.45 (m, 1H) 7.48-7.66 (m, 2H) 7.79 (d, J=8.34 Hz, 1H) 7.88-8.00 (m, 1H) 8.16 (d, J=8.34 Hz, 1H) 11.34 (s, 1H). LC/MS: MS (ES+) m/e 307.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:18]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 110.2 %

Procedure:
To a solution of methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.72 g, 13.2 mmol) and DIPEA (4.85 mL, 27.78 mmol) in DCM (100 mL) was added methyl chloroformate (1.431 mL, 18.48 mmol) in DCM (50 mL) over 30 minutes. The reaction solution was stirred overnight (16 h). The organic phase was washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 110%) as a yellow oil. MS m/z 326, 328 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:18]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cccc(C)c1C(=O)n1cc(F)c(N=CN(C)C)nc1=O
Temperature: 40 °C
Yield: 36.9 %

Procedure:
To an 8 mL screw-cap vial were added pyridine (2 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and 2,6-dimethylbenzoyl chloride (102 mg, 0.60 mmol). The mixture was heated to 40° C. for 2 h, evaporated to dryness, and partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered, evaporated, and the residue was purified by reverse phase chromatography to yield the title compound as a white solid (63 mg, 37%): mp 120-150° C.; 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 8.22 (d, J=6.04 Hz, 1H), 7.23-7.17 (m, 1H), 7.07-7.01 (m, 2H), 3.27 (s, 3H), 3.24 (s, 3H), 2.24 (s, 6H); ESIMS m/z 317 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C@@H:19]([CH2:27][NH:28][CH3:29])[C@H:18]([C:30](O)=O)[C:17]=2[CH:33]=1.Cl>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C@H:19]3[CH2:27][N:28]([CH3:29])[CH2:30][C@@H:18]3[C:17]=2[CH:33]=1
Reactant: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1

Procedure:
To a first reaction vessel containing tetrahydrofuran (2.4 mL) at 0° C. was added aluminum chloride (167 mg, 1.26 mmol). To the resulting suspension was slowly added lithium aluminum hydride (3.77 mmol). To a second reaction vessel containing THF (4 mL) was added trans-8-chloro-10,11-dihydro-11-[(methylamino)methyl]-dibenz[b,f]oxepin-10-carboxylic acid hydrochloride (I).HCl (0.4 g, 1.26 mmol). At −10° C., the contents of the first reaction vessel were added to the second reaction vessel. After 30 minutes the reaction mixture was quenched with water and extracted with toluene. The toluene was dried with magnesium sulfate and evaporated. This provided crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (A) in nearly quantitative yield with a purity of 63%; 1H-NMR (400.13 MHz in CDCl3 relative to TMS) δ 2.54 (s, 3H), 3.15 (m, 2H), 3.25 and 3.61 (2×m, 4H), 7.01-7.36 (m, 7H).