Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][S:44]([OH:46])=[O:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][S:44]([OH:46])=[O:45])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: NCCCS(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCS(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added compound (25) (100 mmol), 3-aminopropylsulfinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (39) as a white solid.
Reaction SMILES: [NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)O

Procedure:
Morpholino-Ser(OAloc) was prepared from SER(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholineacarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccco1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Br)o1

Procedure:
To a one-neck-flask charged with 2-acetylfuran (5.51 g, 50 mmol) in DMF (40 ml) at 0° C., was added N-Bromosuccinimide (9.79 g, 55.0 mmol) portionwise with stirring. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water (400 mL), extracted with ether (150 mL×3). The combined organic layers was dried, concentrated and purified on a silica gel column (Hexanes:EtOAc=4:1) to afford a white solid GC-4-89 (3 g, 31.7%). 1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=3.6 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 2.46 (s, 3H)
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][CH:39]2[C:48]3[N:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH2:42][CH2:41][CH2:40]2)[CH:32]=1)(=[O:30])=[O:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[CH2:16][N:38]([CH2:37][C:33]1[CH:32]=[C:31]([S:28]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=1)[CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: O=S(=O)(NCc1ccccn1)c1cccc(CNC2CCCc3cccnc32)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(NCc1ccccn1)c1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Yield: 46.9 %

Procedure:
Using general procedure B: Reaction of 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-2-carbaldehyde (192 mg, 0.70 mmol), N-Pyridin-2-ylmethyl-3-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzenesulfonamide (284 mg, 0.70 mmol), acetic acid (0.2 mL) and sodium triacetoxyborohydride (442 mg, 2.08 mmol) in THF (7 mL) at room temperature under N2 for 40 min., followed by purification of the crude material by chromatography on silica gel (1:1:98 CH3OH—NH3H2O—CH2Cl2,), afforded the title compound (177 mg, 38%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[C:13]([C:17]1[N:21]=[C:20](Cl)[S:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[C:13]([C:17]1[N:21]=[C:20]([O:9][C:7]2[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[S:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1nsc(Cl)n1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2nc(C(C)(C)C)ns2)c(C)cc1N
Temperature: 100 °C
Yield: 90 %

Procedure:
754 mg (5.50 mmol) of 2,5-dimethyl-4-hydroxyaniline are dissolved in 5 ml of N,N-dimethylformamide and slowly treated with 242 mg (6.05 mmol) of sodium hydride. The reaction mixture is stirred for 15 min, before 972 mg (5.50 mmol) of 3-(tert-butyl)-5-chloro-1,2,4-thiadiazole are added. Subsequently, the reaction mixture is heated at 100° C. for 1 h and then cooled down to AT. After addition of 20 ml of ethyl acetate, the solution is extracted three times with water and dried over MgSO4, and the solvent is removed under vacuum (1.46 g, 94% purity, 90% yield, log P (pH 2.3)=3.29).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 3.8 mg, 0.095 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (21 mg, 0.087 mmol) in THF (0.5 mL) at 0° C. After 1 h at 0° C. rt, 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (prepared in accordance with example 7, step 1, crude, ˜0.095 mmol) in THF (0.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 17.5 h at rt, the reaction was quenched with acetic acid (50% aqueous, 5 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 14 mg (42%) of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].C(OC([N:46]1[CH2:50][CH2:49][CH:48]([CH2:51][C:52](O)=[O:53])[CH2:47]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:52](=[O:53])[CH2:51][CH:48]1[CH2:49][CH2:50][NH:46][CH2:47]1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid as the starting materials in 51% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 9.00 (s, 1H), 8.72 (m, 2H), 8.31 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.68 (s, 1H), 7.30 (d, 1H), 7.08 (d, 1H), 3.98 (s, 2H), 3.40 (m, 1H), 3.27 (m, 1H), 2.97 (m, 4H), 2.58 (m, 2H), 2.11 (m, 1H), 1.61 (m, 2H). LCMS for C23H25ClN7O (M+H)+: m/z=450.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: 90 °C
Yield: 75 %

Procedure:
A microwave vial was charged with 5-bromo-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (Intermediate W) (0.508 g, 1.395 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.469 g, 2.092 mmol), potassium phosphate (0.888 g, 4.18 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.099 g, 0.139 mmol). The vial was sealed with a septum cap and flushed with N2. Dioxane (3.49 mL) and water (1.162 mL) were added and the mixture was sparged for 5 min with N2. The mixture was heated in a microwave at 90° C. for 30 min. The resulting mixture was diluted with EtOAc (5 mL) and decanted from insoluble solids. The resulting solution was concentrated for purification by MPLC. The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a 98:2 Heptane:EtOAc (with 5% EtOH additive) to 100% EtOAc (5% EtOH additive) gradient to afford 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.485 g, 1.046 mmol) as a orange amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[N:13][C:14]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])[CH2:3]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([CH:34]([CH:41]2[CH2:43][CH2:42]2)[CH2:35][C:36]([O:38]CC)=[O:37])[CH:29]=1.[H-].[Na+].Cl>C1COCC1>[CH:41]1([CH:34]([C:30]2[CH:29]=[C:28]([O:25][CH2:24][C:11]3[CH:12]=[N:13][C:14]([C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=4[F:23])=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][C:2]([CH3:26])([CH3:1])[O:6][CH2:5]4)[CH:10]=3)[N:33]=[CH:32][N:31]=2)[CH2:35][C:36]([OH:38])=[O:37])[CH2:43][CH2:42]1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC2COC(C)(C)C2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC2COC(C)(C)C2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
To a solution of (5-((5,5-dimethyltetrahydrofuran-3-yl)methoxy)-6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol (180 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (140 mg) in THF (5.0 mL) was slowly added 60% sodium hydride (60 mg) at 0° C. by small portions, and the mixture was stirred at 50° C. for 3 hr. The mixture was acidified with 1N hydrochloric acid at 0° C. and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (10 mM NH4HCO3-containing system)), and the obtained fraction was evaporated under reduced pressure to give the title compound (40 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)[O:9][C:4]=2[C:3]=1[CH2:22][CH2:23][CH3:24].Cl.[CH2:26](O)[CH3:27]>C(OCC)(=O)C>[OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:26][CH3:27])=[O:15])=[CH:12][CH:11]=3)[O:9][C:4]=2[C:3]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(O)ccc2c(=O)cc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c(=O)cc(-c3ccc(C(=O)OCC)cc3)oc12

Procedure:
The solid acid product of step (a) (5.0g) was suspended in dry ethanol and the mixture saturated with hydrogen chloride, following which dissolution of the solid occurred. The solution was refluxed for 1 hour and evaporated to dryness. The solid obtained was dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate, filtered and evaporated to leave a pink solid. The solid was recrystallised from aqueous ethanol to give 3.5g of ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoate, melting point 225°-6°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[S:13]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:16]=2[N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:19]2[CH2:20][CH2:21][C:22]3[S:13][CH:14]=[N:15][C:16]=3[CH2:17][CH2:18]2)[N:7]=1
Reactant: c1nc2c(s1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ncsc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1a) was treated with the 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-yl)-3H-pyrimidin-4-one as yellow amorphous solid; MS: (M−H]−=306.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH:18]=[CH2:19])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].B.[O:21]1CCCC1.O.ClC(Cl)(Cl)C1N2CCCC2C(=O)O1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][OH:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:4]
Reactant: C1CCOC1
Reactant: C=CCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Agent: B
Agent: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Solvent: O
Product: COC(=O)C1(CCCO)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-allylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25.0 g) in tetrahydrofuran (125 ml) cooled to 0° C. was added dropwise borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution, 105 ml) over 30 minutes, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture was added dropwise additional borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution, 11 ml), and the mixture was stirred at the same temperature for 50 minutes. To the reaction mixture was added dropwise water (180 ml) over 30 minutes and added sodium peroxoborate 1 hydrate (12.0 g) in small batches. The mixture was warmed to room temperature and stirred overnight, and then thereto was added water (500 ml). The mixture was extracted with ethyl acetate (600 ml). The separated organic layer was washed with 20% aqueous sodium thiosulfate solution (600 ml) and saturated aqueous sodium chloride solution. The separated aqueous layer was extracted with ethyl acetate (300 ml, 200 ml) twice. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1 to 1/1) to give the titled compound (17.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCC1CCC1
Product: Cc1cc(C#Cc2cn(CC3CCC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=266.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromomethyl-cyclobutane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][CH:44]([CH2:43][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:22])=[CH:16]5)=[N:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCC5CCN(C(=O)OC(C)(C)C)CC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (423 mg, 1.45 mol), (prepared as described for the starting material in Example 82), triphenylphosphine (685 mg, 2.61 mmol), 4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (500 mg, 2.32 mmol), (prepared as described for the starting material in Example 10), and diisopropyl azodicarboxylate (528 mg, 2.61 mmol) in methylene chloride (18 ml) was stirred overnight at ambient temperature. The mixture was then poured onto a column of silica and eluted with ethyl acetate. After evaporation of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (478 mg, 68%).
Reaction SMILES: C.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:5][N:4]=1.O.NN>CO>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)cnc1N
Reaction time: 12 h
Yield: 63.9 %

Procedure:
0.051 g of ferric chloride and 0.085 g of activated charcoal are added to a suspension of 0.35 g of 2-amino-5-(3,4-dichlorphenyl)-3-nitropyridine (starting material G2) in 10 ml of methanol and the mixture is heated under reflux. 0.270 ml of hydrazine hydrate are added slowly and reflux is continued for 12 hours. After cooling the mixture is filtered and the filtrate is evaporated. The residue is partitioned between sodium-EDTA-solution (0.25M; pH 9–10) and dichloromethane. The organic phase is evaporated to give 0.20 g of the title compound as a yellowish solid of m.p. 202–204° C. The mass spectrum shows the molecular peak MH+ at 254.2 Da.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7][CH2:6]1.[C@@H:21]12[C:30](=O)[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[ClH:32]>N1C=CC=CC=1.C(O)C>[ClH:32].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]4[C:27](=[O:28])[C@H:22]5[C@H:21]([CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30]4=[O:29])[CH2:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g, 10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3 mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column. The pure product thus obtained weighed 2.5 g (67%). This was converted to the hydrochloride salt by treatment with HCl in ethanol (50 ml). The cis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dione hydrochloride crystals so obtained weighed 3.0 g, m.p.=242°-245° C.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[NH:6][CH:7]=[CH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:8]1[C:9](=[O:10])[C:4]2[CH:3]=[C:2]([CH3:1])[S:11][C:5]=2[NH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: Cc1cc2c(=O)cc[nH]c2s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc2c(=O)c([N+](=O)[O-])c[nH]c2s1
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a solution of 1.65 g of 2-methylthieno[2,3-b]pyridin-4(7H)-one 1 in 45 ml of acetic acid is added dropwise a solution of 1.24 g of concentrated nitric acid (d=1.38) in 5 ml of acetic acid at 110° C. The mixture is heated with stirring at the same temperature for 10 minutes and left on cooling. The resulting crystals are collected by filtration and washed with ethyl acetate to give 1.07 g (51%) of Compound 2 as pale yellow crystals melting at 280°-282° C. (dec.).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:20][CH2:21]O)[C:14]=3[CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][C:19]2[N:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=[CH:13][C:14]1=2
Reactant: OCCC1CCCc2c1cnn2-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCC1CCCc2c1cnn2-c1ccccc1
Temperature: 90 °C
Yield: 76 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethanol (516 mg, 2.13 mmol) in 25 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure, to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol, 76%, oil).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH2:13][CH3:14])=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 99.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (2.4 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.4 g) described in Preparation Example 99, the title compound (4 g) was obtained.