Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][C:2]1[S:6][C:5]([C:7]2([CH2:13][NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:25]4[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=4)[CH:29]=3)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Cc1sc(C2(CN)CCOCC2)nc1-c1ccccc1
Product: Cc1sc(C2(CNC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CCOCC2)nc1-c1ccccc1
Yield: 89 %

Procedure:
This compound was synthesized from (4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (55 mg, 89% yield): 1H NMR (300 MHz, CDCl3) δ 8.48 (t, J=1.1 Hz, 1H), 8.23 (dt, J=6.2 Hz, 1.1, 1H), 7.98 (dt, J=7.9 Hz, 1.1 Hz, 1H), 7.74 (bs, 1H), 7.64 (m, 2H), 7.49 (t, J=7.7 Hz, 1H), 7.39-7.29 (m, 2H), 3.92 (m, 2H), 3.85 (d, J=5.7 Hz, 2H), 3.74 (m, 2H), 2.59 (s, 3H), 2.24 (m, 2H), 1.95 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O3S: 528.14. found: 529.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][Cl:7])[CH3:2].C(O)C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>[N+](C)([O-])=O>[Cl:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH2:2][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCc1ccccc1
Reactant: CCOC(CCCl)OCC
Agent: CS(=O)(=O)O
Solvent: C[N+](=O)[O-]
Product: CCOC(CCCl)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Chloropropionaldehyde diethyl acetal (LXII, 30.66 g, 0.184 mol) is added to an ice-cooled solution of phenethyl alcohol (XLV, 20.44 g, 0.167 mol) in nitromethane (50 ml) is added and methanesulfonic acid (1.61 g, 0.0167 mol). After 30 min the ice bath is removed and the mixture is allowed to stir overnight. The mixture is then warmed in a water bath at approximately 40°-50° under reduced pressure for 10-20 min (no appreciable removal of nitromethane occurs but there is some further reaction observed). The mixture is partitioned between ethyl ether and saline, the layers are separated and the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The crude material is stored overnight in the refrigerator and then chromatographed on silica gel eluting with hexane and then ethyl acetate/hexane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 2.05, 2.87, 3.43-3.86, 4.69 and 7.24 δ.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])=[N:7][CH:8]=1.[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([O:39][CH2:2][C:3]3[CH:8]=[N:7][C:6]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[F:17])=[C:5]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=3)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(F)c(-c2ncc(CBr)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1ccnc(O)c1)C1CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(OCc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A mixture of 5-(bromomethyl)-2-(2-fluoro-5-methoxyphenyl)-3-neopentylpyridine (88 mg), ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propanoate (62 mg), silver carbonate (72.6 mg) and toluene (2.0 mL) was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature and filtered. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28 mg) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(Cc4ccccc4)CC(F)(F)F)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 50 mg (0.15 mmol) 6-chloropyrimidine-4-carboxylic acid-benzyl-(2,2,2-trifluorethyl)-amide and 34 μL (0.20 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(=O)CCC1=O>CC1CCCO1>[Br:14][C:12]1[CH:11]=[N:10][N:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)(C)n1cccn1
Solvent: CC1CCCO1
Product: CCOC(=O)C(C)(C)n1cc(Br)cn1

Procedure:
Ethyl 2-methyl-2-(1H-pyrazol-1-yl)propanoate 17 was reacted with N-bromosuccinimide (NBS) in 2-methyltetrahydrofuran to give IV (CAS Reg. No. 1040377-17-0).
Reaction SMILES: [O:1]=[C:2]1[CH:17]2[CH:5]([CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=32)[C:4](=[O:24])[NH:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CC(C)=O.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[C:4](=[O:24])[NH:3]1
Reactant: O=C1NC(=O)C2C(c3ccccc3)Cc3[nH]c4ccccc4c3C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccccc3c21

Procedure:
1.2 g (3.8 mmole) 1,2,3,3a,4,5,6,10c-octahydro-1,3-dioxo-4-phenylpyrrolo[3,4-c]carbazole and 2.2 g (9.7 mmole) DDQ are heated under reflux for 20 hours in 30 ml toluene. The solvent is distilled off in a vacuum and the residue chromatographed on silica gel with toluene/ethyl acetate 3:1. The fraction with the Rf of 0.3 is isolated, stirred up with acetone/diisopropyl ether, and the crystals formed are filtered off. One obtains 1,2,3,6-tetrahydro-1,3-dioxo-4-phenyl-pyrrolo[3,4-c]carbazole in the form of yellow crystals of the mp 262°-263° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(C)c2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(3-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (208 mg, 0.656 mmol) in a mixture of MeOH (10.0 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H3, (192 mg, 97%); Rt 1.19 min (Method 2); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [Si]([O:8][C@H:9]([C:40](=[O:42])[NH2:41])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.Cl.O.CC#N>ClCCl>[CH2:38]([NH:30][CH:27]1[CH2:28][CH2:29][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][C@H:9]([OH:8])[C:40]([NH2:41])=[O:42])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:25][CH2:26]1)[CH3:39]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Into a 50-mL round-bottom flask was placed a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (160 mg, 0.26 mmol, 1.00 equiv) and hydrogen chloride (conc.) (0.3 mL) in dichloromethane (3 mL). The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-015(Waters)): column: Xbridge Prep C18, 5 um, 19*50 mm; mobile phase: water with 50 mmol NH4HCO3 and CH3CN (10% CH3CN up to 25% in 10 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: 254/220 nm. 47.3 mg product was obtained. This resulted in 47.3 mg (45%) of (2S)-3-[(3R)-12-[[4-(ethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2-hydroxypropanamide as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.474 (1H, s), 5.24-5.26 (1H, m), 4.08-4.12 (1H, d), 3.53 (1H, m), 3.04-3.28 (1H, m), 2.92-2.95 (1H, m), 2.50-2.71 (4H, m), 2.40-2.47 (2H, m), 2.15-2.23 (2H, m), 1.98-2.07 (2H, m), 1.61-1.96 (3H, m), 1.26-1.34 (2H, m).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>COCCOC>[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C1CCN(C(=O)OCC)CC1
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a suspension of 4 g oily sodium hydride (60%) in 200 ml of anhydrous 1,2-dimethoxyethane, was added dropwise 23.6 g ethyl diethylphosphonoacetate at about 20° C., and the mixture was stirred at that temperature for about one hour. To the solution thus obtained, was added dropwise 17.1 g N-ethoxycarbonyl-4-piperidone at temperatures below 30° C., the mixture was stirred for an additional two hours, and the solvent was distilled off under reduced pressure. Ice water (100 ml) and ethyl acetate (100 ml) were added to the residue, the mixture was shaken, and the layers were separated. The aqueous layer was extracted twice with 100 ml ethyl acetate, and all the organic solutions were combined, washed with water and dried over anhydrous magnesium sulfate. Distilling off the solvent from the dried solution gave 25.7 g of ethyl N-ethoxycarbonyl-4-piperidylideneacetate as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[C:14]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Li+]>[Br:12][C:13]1[C:14]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[CH:27][CH:28]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: Nc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)OCO3)cc1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (113 mg, 640 μmol) was added to a stirred solution of 80 (125 mg, 430 μmol) and Hünig's base (224 μL, 166 mg, 1.28 mmol) in dichloromethane (2.1 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (2 mL), methanol (2 mL) and 1.2 M lithium hydroxide solution (1 mL). The mixture was stirred and heated to 60° C. for 5 min then cooled to room temperature, diluted with dichloromethane and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 81 (99.2 mg, 54%) as a solid: LRESIMS m/z 432.0 [M+H]+, calcd. for C20H13Br1F2N1O3 432.0.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]([CH:29]1[CH2:31][CH2:30]1)([CH3:28])[CH2:24][C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH2:24][C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]2([F:1])[CH2:3][O:4][CH2:5]2)=[CH:11][N:10]=1)=[O:14])([CH:29]1[CH2:31][CH2:30]1)[CH3:28]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: CC(N)(CC(N)=O)C1CC1
Product: C[C@H](Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 39%); MS (ESI, m/z): 434.3 (M+H+).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[Cl:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C#N)cc1Cl
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-chloro-4-methoxybenzonitrile (0.757 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 84% yield) as a solid after drying. MS: MS m/z 316.1 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]2[C:12]([CH2:13][CH2:14]CCCCCCCCC)=[N:11][N:10]=[C:9]2[CH2:24][OH:25])=[C:5]([C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1[S:7][C:6]2[N:8]3[C:12]([CH2:13][CH2:14][CH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH2:26][CH2:27][CH2:28][CH3:29])=[N:11][N:10]=[C:9]3[CH2:24][O:25][CH:26]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCCCCCCCCCCc1nnc(CO)n1-c1sc(CC)cc1C(=O)c1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCc1nnc2n1-c1sc(CC)cc1C(c1ccc(O)cc1)OC2
Yield: 122.2 %

Procedure:
5-Ethyl-3-(4-hydroxybenzoyl)-2-(3-hydroxymethyl-5-undecyl-1,2,4-triazol-4-yl)thiophene (11 g) obtained in Example 21 was dissolved in ethanol (60 ml). Thereto was added sodium borohydride (431 mg) with stirring and the mixture was stirred at room temperature for 1 hour. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added to the residue and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (150 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the oily substance obtained was crystallized from isopropyl etherethyl acetate (4:1) to give 6.5 g of 2-ethyl-4-(4-hydroxyphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine as white brown crystals, melting point 96°-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2C)c(N)n1
Product: COc1ccc(F)c(C)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(3-fluoro-6-methoxy-2-methyl-phenyl)-methanone (Example 350) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(3-fluoro-6-methoxy-2-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 402.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:15][OH:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:18]=1[O:16][CH2:15][C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A suspension of NaH (60% in mineral oil, 1.48 g, 36.9 mmol, Eq: 2.10) inDMF (15 mL) was cooled to 0° C. and (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.61 g, 17.6 mmol, Eq: 1.00) in DMF (15 mL) was added dropwise over 15 min. The mixture was stirred at 0° C. for 30 min. and at room temp. (RT) for 30 min. The mixture was cooled to 0° C. and methyl 2-fluoro-3-nitrobenzoate (3.5 g, 17.6 mmol, Eq: 1.00) in DMF (15 mL) was added dropwise over 10 min. After 2.5 h the mixture was diluted with ice cold H2O and extracted with EtOAc. The combined extracts were dried over Na2SO4 filtered and concentrated to give a residue that was purified by chromatography to afford 2-((S)-2-tert-butoxycarbonylamino-2-carboxy-ethoxy)-3-nitrobenzoic acid methyl ester (4.3 g, 50%) as a yellow foam.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[C:14]1[CH:20]=[C:19](O)C=[CH:17][C:15]=1O>CO>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:17][CH2:15][CH2:14][CH2:20][CH3:19]
Reactant: Cc1cc(O)ccc1O
Reactant: CCC=CCCCCCCCC
Solvent: CO
Product: C=CCCCCCCCCCCCCCCC
Reaction time: 17 h

Procedure:
8-methoxycarboniltetracyclo [4.4.0.12,5.117,10]-3-dodecen of 65 grams, dicyclopentadien of 87 grams and methylhydroquinon of 0.14 gram were mixed in a 300 milli-litter eggplant type flask, and the reaction was continued at 170 degrees to 180 degrees in centigrade for 17 hours. The reaction product remained cooled, and residual 8-methoxycarboniltetracyclo [4.4.0.12,5.117,10]-3-dodecen and residual dicyclopentadien were distillated in vacuum. Hot methanol was added to the residue, and insoluble content was filtrated. The filtrate was concentrated in vacuum, and residue was recrystallized from methanol. Then, we obtained white crystal of 12-methoxycarbonilhexacyclo [6.6.1.13,6.110,13.02,7.09,14] heptadecen of 10 grams.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[CH3:11])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH3:12][N:9]1[C:10]([CH3:11])=[C:6]([CH2:5][CH:4]=[O:3])[C:7]([CH3:13])=[N:8]1
Reactant: CCOC(=O)Cc1c(C)nn(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1CC=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve (1,3,5-trimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.8 g, 14.3 mmol) in tetrahydrofuran (200 mL) and cool to −78° C. Add diisobutylaluminum hydride (42.8 mL, 42.8 mmol, 1 M in toluene) dropwise over 30 min. Stir an additional 2 hr. at −78° C. Partition between saturated aqueous potassium sodium tartrate solution (150 mL) and ethyl acetate (500 mL) and stir for 16 hr. at room temperature. Separate organic layer, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate), to give the title preparation (0.26 g, 12%). 1H NMR (CDCl3) δ 9.54 (t, 1H), 3.71 (s, 3H), 3.38 (d, 2H), 2.15 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]([C:22]([O:24]CC)=[O:23])([C:17]([O:19]CC)=[O:18])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]([C:17]([OH:19])=[O:18])([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2onc(-c3ccc(Cl)cc3)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCc2onc(-c3ccc(Cl)cc3)c2C1
Yield: 102.2 %

Procedure:
7.7 g of diethyl 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5,5-dicarboxylate were treated with 2.74 g of potassium hydroxide in 16 ml of water and 65 ml of ethanol at 20° C. for 3 days. After removal of the ethanol by evaporation and acidification with 2N hydrochloric acid, the product was taken up in ethyl acetate. There were obtained 6.7 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5,5-dicarboxylic acid as a buff colored solid of melting point 200°-202° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:26])[CH3:25])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(C)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and acetic acid to yield (3aR,4S,7aR)-4-acetoxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); =6.041 min; LC-MS Method II