Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[C:11]([CH:16](OC)[C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([Cl:28])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(c1c(F)ccc(OCc2ccccc2)c1Cl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1ccc(OCc2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12
Yield: 84.5 %

Procedure:
A mixture of 3-[(3-Benzyloxy-2-chloro-6-fluoro-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (P-1867, 0.1 g, 0.2 mmol), trifluoroacetic acid (0.6 mL, 8 mmol), and triethylsilane (0.3 mL, 2 mmol) in acetonitrile (10 mL) was refluxed for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide compound as an off-white solid (P-1852, 62 mg, 70%). MS (ESI) [M+H+]+=367.16.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)=[O:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)=[O:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][NH:7][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(NC(=O)Nc2cnc(C#N)cn2)cc1Cl)Cc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)Nc2ccc(OCCNCc3ccc(F)cc3F)c(Cl)c2)cn1
Temperature: 40 °C
Yield: 10.1 %

Procedure:
To a solution of tert-butyl 2-(2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)phenoxy)ethyl-(2,4-difluorobenzyl)carbamate (0.53 g, 0.95 mmol) in tetrahydrofuran (5 mL) at 0° C. was added trifluoroacetic acid (1.19 g, 9.5 mmol), and the resulting mixture was heated at 40° C. for 12 hours. The solvent was removed under reduced pressure to leave a residue that was purified by preparative HPLC (Preparative HPLC Method 1) to give the title compound (44 mg, 10%).
Reaction SMILES: [CH:1]1([C:7]2[CH:24]=[CH:23][C:10]([O:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([CH3:22])[CH:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl>[CH:1]1([C:7]2[CH:24]=[CH:23][C:10]([O:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([NH2:19])=[C:14]([CH3:22])[CH:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2ccc(C3CCCCC3)cc2)c(C)cc1N
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A solution of 0.49 g (1.5 mmol) of 4-(4-cyclohexylphenoxy)-2,5-dimethylnitrobenzene in 7 ml of dioxane and 7 ml of hydrochloric acid is admixed with 1.01 g (4.5 mmol) of tin(II) chloride dihydrate at room temperature and the mixture is then refluxed for 2 h. It is cooled to room temperature, neutralized with aqueous NaHCO3 and extracted repeatedly with dichloromethane, and the extracts are dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (0.29 g, purity 95.2%, yield 61.5%, log P (pH 2.3)=4.25).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC2(CC1)OCCO2
Yield: 97.3 %

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester (1.10 g, 4.86 mmol) was dissolved in 30 ml ethyl acetate and stirred with 110 mg Pd/C 10% under hydrogen atmosphere for 4 hours. The catalyst was filtered off and the solvent evaporated. The crude product (1.08 g, 97%) [MS: m/e=229.3 (M+H+)] was obtained as a colourless liquid and used without any further purification for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.[OH-].[Na+]>[NH:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10][CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCCNCC1)C3
Yield: 19 %

Procedure:
A solution of (R)-4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-azepane-1-carboxylic acid tert-butyl ester (173 mg; 0.31 mmol; 1 eq.) in a 4M solution of HCl in 1,4-dioxane (2 mL) was stirred at room temperature for 16 hours. The residue was diluted with 0.1M NaOH and extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (27 mg, 17%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 7.37 (ddd, J=8.5, 6.8, 3.2 Hz, 1H), 7.12 (dd, J=11.8, 2.3 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 4.88-4.72 (m, 2H), 4.54 (d, J=15.8 Hz, 2H), 3.10-2.74 (m, 7H), 2.61 (s, 1.5H), 2.56 (s, 1.5H), 2.11-1.49 (m, 6H). HPLC (max plot) 96.2%, Rt 2.91 min. UPLC/MS: (MS+) 458.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1

Procedure:
The alkylating agent used, cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane (mass spectrum (ESI+): m/z=370 [M+H]+) was prepared by reacting cis-4-(tert.butyloxycarbonylamino)-cyclohexanol with 4-methylphenyl-sulphonyl chloride in pyridine.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>CN(C=O)C.O>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:23]=[CH:22][C:21]4[C:17](=[CH:18][N:19]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[N:20]=4)[CH:16]=3)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3nn(CC(=O)N(C)C)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), potassium iodide (1 mg) and 2-chloro-N,N-dimethylacetamide (140 mg; 1.15 mmol). After stirring at RT for 72 hours the mixture was poured in water (20 ml) and stirred at RT for 1 hour. The solid was removed by filtration, washed with water and dried. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid, together with 6-[(cyclopropylmethyl)(propyl)amino]-N-{1-[2-(dimethylamino)-2-oxoethyl]-1H-indazol-5-yl}pyrimidine-4-carboxamide (Example 115 below).
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[F:15].[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH2:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:15][C:3]1[C:4](=[O:14])[N:5]2[C:9](=[C:10]([C:11]([OH:13])=[O:12])[C:2]=1[NH:19][C:18]1[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:17]=1[F:16])[CH2:8][CH2:7][CH2:6]2
Reactant: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCC2
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
Compound 1d (240 mg, 1.04 mmol) and 2-fluoro-4-iodoaniline (493 mg, 2.08 mmol) stirred in dry THF (10 ml) at 0° C. under nitrogen. LiHMDS (1M in THF, 3.11 mL, 3.11 mmol) was added dropwise, and the reaction stirred 4 h while warming to RT. The solution was quenched with 1N HCl and extracted with 10% MeOH/CH2Cl2 (3×). Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (10% to 16% MeOH/CH2Cl2) gave 238 mg (53%) of Example 1 as a tan solid. 1H NMR (400 MHz, MeOD-d4): δ 7.22-7.31 (m, 2H), 6.67 (t, 1H, J=8.0 Hz), 4.06 (t, 2H, J=7.6 Hz), 3.45 (t, 2H, J=7.6 Hz), 2.05-2.15 (m, 2H). MS (ES) [m+H] calc'd for C15H11F2IN2O3, 433. found 433.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:16]([O:19][CH2:20][CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH2:23]1)(=[O:18])[CH3:17]>>[Si:8]([N:25]1[CH:22]([CH2:21][CH2:20][O:19][C:16](=[O:18])[CH3:17])[CH2:23][C:24]1=[O:26])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OCCC1CC(=O)N1
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
Triethylamine (Et3N) (2.96 ml, 21.2 mmol) and t-butyldimethylsilyl chloride (3.059 g, 20.3 mmol) are added to an ice-cold stirring solution of 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g, 19.3 mmol) in anhydrous dimethylformamide(DMF) (20 ml). A white precipitate appears immediately. The cooling bath is removed and the mixture is stirred at 25° C. (room temperature) for 5 mins. The mixture is diluted with benzene (200 ml), washed with H2O (5×80 ml) and brine, dired with MgSO4, filtered, and evaporated under reduced pressure to afford N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (5.078 g) as an off white solid: ir(neat) 5.75, 8.08, 8.41, 11.92, and 12.18 cm-1 ; nmr (CDCl3) δ0.25 (s, 6), 0.98 (s, 9), 1.97 (m, 2), 2.05 (s, 3), 2.67 (dd, 1), 3.20 (dd, 1) 3.62 (m, 1), and 4.12 (t, 2); mass spectrum m/e 214 (M+ - 57) and 172.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])[C@@H:9]([CH3:11])[OH:10]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:4]([O:3][CH:1]([O:10][C@H:9]([CH3:11])[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:2])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C=COCC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Temperature: 25 °C
Yield: 86.7 %

Procedure:
24.0 g of dehydrated isobutyl vinyl ether was dropwise added to a mixture of 32.7 g of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride which was being stirred at room temperature, so that the internal temperature of the reaction system could be kept at 40° C. or less. Then, the resulting mixture was stirred at room temperature overnight. After the reaction, thereto was added 200 ml of ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 47.8 g (yield: 96.9%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(OC(C)(C)C)=O)=[C:6]([NH:18][CH3:19])[CH:5]=1.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:18][CH3:19])[CH:5]=1
Reactant: CNc1cc(C(=O)OC)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving 4-tert-butoxycarbonylamino-3-methylaminobenzoic acid methyl ester (794.3 mg, 2.83 mmol) in methanol (7.0 ml), a 4N hydrogen chloride-1,4-dioxane solution (3.54 ml, 14.3 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 30 minutes. An equivalent amount of the 4N hydrogen chloride-1,4-dioxane solution was further added, and the mixture was stirred at 40° C. for 30 minutes. The reaction mixture was poured into ice-cooled saturated aqueous sodium bicarbonate, and was extracted with ethyl acetate (30 ml×3). The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→3/2→1/1) to obtain 4-amino-3-methylaminobenzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Oc1ccccc1
Product: CC(C)(C)CN(CCOc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and phenol: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=9.0 Hz, 1H), 7.31-7.23 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 6.69 (app. t, J=7.3 Hz, 1H), 6.91 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d, J=8.2 Hz, 2H), 4.11 (t, J=5.7 Hz, 2H), 3.93 (t, J=5.7 Hz, 2H), 3.40 (s, 2H), 1.01 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC(Br)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a 500 mL flask, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (20 g, 93%, 55.92 mmol), ethanol (100 mL) were added. The solution of sodium hydroxide (2.34 g, 58.50 mmol, dissolved into water (100 mL)) was added dropwise. After being stirred for 2 hours at room temperature, the reaction mixture was concentrated by rotary evaporator to remove ethanol. Aqueous solution was extracted with ethyl acetate (30 mL) and acidified with concentrated hydrochloric acid to pH=3. Then aqueous solution was extracted with ethyl acetate (3×100 mL) again. The organic layers were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (16.67 g) as a yellow solid in 92% yield. HPLC area normalization method content is 94% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C84.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=O)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[Br-].[CH3:22][O:23][C:24]([CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2/[C:8](=[CH:26]/[C:24]([O:23][CH3:22])=[O:25])/[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C1\COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Temperature: 70 °C
Yield: 43.5 %

Procedure:
To a stirred solution of 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (100 mg, 0.28 mmol) in THF (7 mL), was added Methoxycarbonylmethyl(triphenyl)phosphonium Bromide (120 mg, 0.28 mmol), NaH (6.8 mg, 0.28 mmol). The reaction mixture was heated to 70° C. overnight. The mixture was cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to afford 9-Bromo-4-[1-methoxycarbonyl-meth-(E)-ylidene]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (50 mg, 43%) as a light yellow solid. LC-MS (ESI & APCI): 412.3 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][N:6]([C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH:22][C:23](=O)[CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][N:6]([C:13]([C:14]1[CH:19]=[CH:18][C:17]2[N:20]([CH3:21])[C:23]([CH2:24][NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=3)=[N:22][C:16]=2[CH:15]=1)=[O:35])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1NC(=O)CNc1ccc(C#N)cc1
Solvent: CC(=O)O
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Yield: 58 %

Procedure:
A solution of the product of 1c (22.6 mmol) in 100 mL concentrated acetic acid was heated to reflux for one hour. The solution was then evaporated to dryness, the remaining solid triturated with water and under stirring the pH was adjusted to about 8-9. The crude product was isolated through extraction with ethyl acetate and purified by chromatography on silica gel (eluent: dichloromethane/ethanol 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@@H:14]([OH:16])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Yield: 84.7 %

Procedure:
To a solution of 4-((1R,2S)-1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (1.63 g, 2.9 mmol) in THF (60 mL) was added TBAF (3.2 mL, 3.2 mmol, 1 M solution in THF) at −50° C. After addition, the reaction mixture was allowed to warm to −20° C. gradually (about 1 h), then quenched by adding saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried over Na2SO4 and filtered. Concentration provided a residue, which was purified by flash chromatography over silica gel to provide the title compound 4-((1R,2S)-1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile (1.10 g, 85%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.79 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.23 (d, J=8.6 Hz, 1H), 4.72 (dd, J=2.5, 8.6 Hz, 1H), 4.62 (m, 1H), 3.01 (d, J=3.5 Hz, 1H), 2.34 (s, 3H), 1.42 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A83) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[N:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=1)[CH3:12])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(Cc1cccc(CO)c1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
Dissolve 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-benzoic acid methyl ester (1.70 g, 6.1 mmol) in tetrahydrofuran (60 mL) at 0° C. Add a 1M solution of lithium aluminum hydride in tetrahydrofuran (8 mL, 8 mmol) dropwise and stir for 2 hrs. Quench the reaction with water (3 mL), 5N sodium hydroxide solution (3 mL) and more water (9 mL), filter and concentrate. Purify the residue by chromatography (silica gel) eluting with 40-60% ethyl acetate/hexanes to provide the title compound (1.42 g, 93%).