Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:21][OH:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>O1CCCC1.O>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:20]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:32])[CH3:33])[CH:21]=[O:22])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[Si](O[C@@H](C=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a −78° C. solution of oxalyl chloride (10.8 mmol) in tetrahydrofuran (45 mL) was added dimethylsulfoxide (21.6 mmol). After stirring for 10 minutes, a solution of the title alcohol of Step 3 (10.8 mmol) in tetrahydrofuran (4.6 mL) was added dropwise. The solution was stirred for 20 minutes at −78° C. and then Et3N (45.1 mmol) was added. The reaction solution as allowed to warm to room temperature over a 2 hour period. The opaque, white mixture was poured into water (50 mL) and then extracted with ether (2×50 mL). The combined organic layer was washed with 1N HCl (50 mL), aqueous 5% NaHCO3 (50 mL), and brine (50 mL). The dried filtrate (MgSO4) was evaporated to give the title aldehyde (4.20 g, 100% yield). The 1H, 13C and APT NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:17](=O)[O:16]C(C)(C)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:18]=1[CH:17]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1c(O)cccc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 5-(benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (Example 38A, 4.00 g, 14.07 mmol) in dichloromethane (80 mL) was cooled to −78° C. and treated with a solution of diisobutylaluminum hydride (6.00 g, 42.2 mmol) in toluene (40 mL) added dropwise over 20 min. The resulting mixture was then stirred at −78° C. for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by 4 N hydrochloric acid (20 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 80 mL of 4N hydrochloric acid was added over 10 min and the mixture was stirred vigorously at 22° C. for 4 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting oil was chromatographed on silica gel (4×10 cm, elution toluene) to give 2.25 g (70% yield) of the title material as a pale yellow solid. LC (Method A): 2.219 min. HRMS (ESI) calcd for C14H13O3 [M+H]+ m/z 229.0859. found 229.0859. 1H NMR (CDCl3, 600 MHz) δ ppm: 5.12 (s, 2H), 6.43 (d, J=8.25 Hz, 1H), 6.52 (d, J=8.46 Hz, 1H), 7.34-7.4 (m, 6H), 10.39 (s, 1H), 11.95 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]([O:18]CC)=[O:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[S:5][CH:4]=[CH:3]1.[OH-].[Na+]>>[O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]([OH:18])=[O:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[S:5][CH:4]=[CH:3]1
Reactant: CCOC(=O)Cn1c2ccccc2c2sccc(=O)c21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c2ccccc2c2sccc(=O)c21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
-- A mixture of 6.0 g (0.021 mole) of ethyl 4,5-dihydro-4-oxothiopyrano[3,2-b]indole-5-acetate and 21 ml of 1N sodium hydroxide solution is stirred for 1/2 hour at 95° C. The clear solution is cooled, acidified and the solid filtered and recrystallized from isopropanol to give 4.9 g of product, mp 275°-278° C.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=O)([C:3](OCC)=[O:4])=[O:2].C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[NH:8]1[C:1](=[O:2])[C:3](=[O:4])[NH:23][C:10]2=[C:11]3[C:16]([CH:17]=[C:9]12)=[CH:15][CH:14]=[CH:13][CH2:12]3
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)NC1Cc2ccccc2C1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c([nH]c1=O)=C1CC=CC=C1C=2
Temperature: 20 °C
Yield: 76.1 %

Procedure:
1.25 g of 2-ethoxalylamino-1-indanone are added rapidly to a solution of 12.5 g of ammonium acetate in 50 ml of acetic acid brought to reflux under nitrogen. After 18 hours of reflux, the reaction medium is cooled to a temperature in the region of 20° C. The precipitate formed is filtered off, washed copiously with water and dried under a partial vacuum (1 mm Hg; 0.13 kPa) at 50° C. 0.77 g of 1,4-dihydro-5H-indeno[1,2-b]pyrazine-2,3-dione are thereby obtained in the form of a green powder, the melting point of which is above 260° C. (analysis C11H8N2O2 ; 1.18 H2O; % calculated C: 66.00; H: 4.03; N: 13.99; % found C: 65.7; H: 3.9; N: 13.9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 80 °C
Yield: 15.9 %

Procedure:
A solution of (4-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA48 (4.5 mg, 16% yield). ESI-MS (M+H)+ m/z calcd 284.1, found 284.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:27][C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])[C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(F)(F)F)C1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (±)-4-oxo-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2b) (1 equiv.) in toluene is added (R)-(+)-α-methylbenzylamine (1 equiv.) and catalytic amount of p-toluenesulfonic acid. The solution is heated to reflux under a Dean-Stark apparatus. After 12 hr, the reaction is cooled to RT, washed with 10% aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue is dissolved in EtOH and NaBH4 (1 equiv.) is added. After 12 h, the reaction is concentrated and the residue is dissolved in 1 N HCl. The solution is neutralized with 6 N NaOH and extracted with EtOAc. The organic fraction is dried over Na2SO4 and concentrated under vacuum. The crude product is purified by chromatography on silica gel to afford the title compound. The three other diastereomers are also separated.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([CH3:23])[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:13]2[C:9]([OH:8])=[N:10][N:11]([CH:24]([CH3:25])[CH3:26])[C:12]=2[CH3:23])=[CH:16][CH:17]=1)[CH3:22]
Reactant: CCc1ccc(Cc2c(OCc3ccccc3)nn(C(C)C)c2C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Cc2c(O)nn(C(C)C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of the thus obtained 3-benzyloxy-4-(4-ethylbenzyl)-1-isopropyl-5-methyl-1H-pyrazole (160 mg, 0.46 mmol) in methanol (3 mL), 20% palladium hydroxide/carbon (58 mg) was added at room temperature and stirred overnight under a hydrogen atmosphere at room temperature. After filtration to remove the insoluble materials, the solvent was distilled off under reduced pressure to give 4-(4-ethylbenzyl)-3-hydroxy-1-isopropyl-5-methyl-1H-pyrazole (109 mg, 92%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([O-:30])=O)[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([NH:1][C:2]4[CH:10]=[CH:9][C:5]5[NH:6][C:7]([C:16]6[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=6)=[N:8][C:4]=5[CH:3]=4)=[O:30])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:17][CH:18]=1)#[N:12]
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Product: N#Cc1ccc(-c2nc3cc(NC(=O)c4ccc5nc(-c6ccc(C#N)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 295 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyano)phenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C29H17N7O: 480.15; found: 479.89.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7](=[O:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=1.[Li+].[OH-].Cl>C(#N)C>[CH3:1][O:2][C:3]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7](=[O:26])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1
Reactant: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.40 g, 2.55 mmol) in acetonitrile (100 mL) was added aqueous 0.10 M LiOH (50 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 1.29 g (98%) of a pale yellow oil.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH2:7]([O:14][CH2:15][CH:16]1[CH2:18][CH:17]1[S:19]([N:22]1[C:26]2[C:27]3[O:31][CH:30]=[CH:29][C:28]=3[C:32]([F:35])=[C:33]([F:34])[C:25]=2[N:24]([C:36]2[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=2[F:43])C1=O)(=[O:21])=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C>C1COCC1.CCCCCC.C(Cl)Cl>[CH2:7]([O:14][CH2:15][CH:16]1[CH2:18][CH:17]1[S:19]([NH:22][C:26]1[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[C:32]([F:35])=[C:33]([F:34])[C:25]=1[NH:24][C:36]1[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=1[F:43])(=[O:20])=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)c3ccoc3c2n1S(=O)(=O)C1CC1COCc1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1CC1COCc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Potassium trimethyl silanolate (0.105 g, 0.8256 mmol) was added to a solution of 1-(2-(benzyloxymethyl)cyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (I-37a: 0.180 g, 0.2752 mmol) in THF (5 mL) at 0° C. The reaction mass was stirred for 2 hours at 20-40° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford 0.160 g of the crude product which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.52 (d, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 7.20-7.26 (m, 5H), 7.20 (bs, 1H), 6.92 (d, 1H), 632-6.39 (m, 2H), 4.48 (s, 2H), 3.25 (q, 2H), 2.52 (q, 1H), 1.52-1.53 (m, 1H), 1.20-1.23 (m, 1H), 0.90-1.01 (m, 1H). LCMS: 93.86%, m/z=627.9 (M-1). HPLC: 95.59%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:70][S:71]([CH2:74][CH2:75][NH2:76])(=[O:73])=[O:72]>CN(C)C=O.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([NH:76][CH2:75][CH2:74][S:71]([CH3:70])(=[O:73])=[O:72])=[O:30])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CC[C@@H]3[C@@H]2C2CCCC2)cc1Cl
Reactant: CS(=O)(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)CC[C@H]1C2=NN(c2ccc(C#N)c(Cl)c2)[C@H]1C1CCCC1
Yield: 52 %

Procedure:
To a solution of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 (90 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole (43 mg, 0.32 mmol), triethylamine (0.06 mL, 0.40 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (103 mg, 0.32 mmol). The solution was stirred for fifteen minutes followed by addition of 2-(methylsulfonyl)ethanamine (40 mg, 0.32 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was quenched with water and the resulting yellow solid was collected by vacuum filtration. Chromatography (reverse phase, acetonitrile/water) provided (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-(methylsulfonyl)ethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide (yellow solid, 55 mg, 52% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.01 minutes (10 to 90% acetonitrile/water over 6 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 525 (M+H)
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Br)=O.O.O.O.O.O.O.O.O.O.[S-2:23].[Na+].[Na+].O.Cl>CCO>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:23][CH:1]=[N:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=CNc1cc([N+](=O)[O-])ccc1Br
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of formamide from Step 1 (5.83 g, 23.8 mmol) and sodium sulfide nonahydrate (8.60 g, 35.8 mmol) in EtOH (120 ml) was heated to reflux for 2 h under nitrogen. After this time the reaction was cooled to RT then poured into cold water (600 ml). The resulting solution was cooled in an ice bath and acidified to pH 1 with 37% HCl. The solution was cooled in an ice bath for a further 1 h, during which time an orange precipitate formed. This solid was isolated by filtration and dried under vacuum to afford 5-nitrobenzothiazole as an orange solid (2.28 g). The above filtrate was extracted with EtOAc (3×200 ml), and the combined organic extracts dried over Na2SO4, filtered and concentrated under vacuum to afford additional 5-nitrobenzothiazole (0.89 g) as an orange solid. NMR and TLC analysis indicated that both crops of product were identical; the combined yield was 3.17 g. 1H NMR (CDCl3) δ 9.19 (s, 1H), 9.02 (d, 1H), 8.35 (dd, 1H), 8.12 (d, 1H); 13C NMR (CDCl3) δ 157.3, 153.1, 147.0, 140.2, 122.5, 120.1, 119.3. MS (ESI+) for m/z 181 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C1CCN2C(=NCCC2)CC1.C(O)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:24])[CH2:21][CH2:22]3)[CH:14]=[C:13]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(C(=O)O)CC2)n1)c1ccc(F)cc1
Reactant: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(C(=O)NS(C)(=O)=O)CC2)n1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Under argon atmosphere, 92 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}piperidine-4-carboxylic acid (Example 85) was dissolved in 2 ml of tetrahydrofuran, and 41 mg of N,N′-carbonyldiimidazole was added thereto, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was air-cooled to room temperature, and 80 mg of methanesulfonamide and 63 μl of 1,8-diazabicyclo[5,4,0]-7-undecene were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, and the pH of the mixture was adjusted to 4 by using acetic acid. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 42 mg of the objective compound as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])[CH3:2].[ClH:22]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Cl:22])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Reactant: Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 80 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (2.1 g, 6.0 mmol) in acetonitrile (30 mL) was added concentrated HCl (1.4 mL, 18.0 mmol). The reaction was stirred for 6 h at 80° C., and then diluted with H2O. The solid was filtered, washed with H2O, and dried to give (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.7 g) which contained ˜20% of the hydrolyzed acid. The aforementioned ester was dissolved in dioxane (10 mL). After addition of 1 N LiOH (9.0 mL), the reaction was stirred for 4 h at 40° C. The reaction was cooled down to room temperature, diluted with H2O, and acidified with 4 N HCl to form a precipitate. The solid was filtered, washed with H2O, and dried to give the title compound. LCMS m/z=276.1 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][CH2:16]CCCC/C=C\CCC.C(OCCCCCCCC=C)(=O)C.C=CCCC>C1COCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: CCC/C=C\CCCCCCCO
Reactant: CCCCCCCC=COC(C)=O
Agent: C=CCCCCCCCOC(C)=O
Solvent: C1CCOC1
Solvent: C=CCCC
Product: CCC/C=C\CCCCCCCOC(C)=O
Yield: 65 %

Procedure:
By cross metathesis of nonenyl acetate: according to the procedure for compound 12, 8-nonenyl acetate (0.76 g, 4.1 mmol) and 1-pentene (4 mL) in THF (4 mL) were reacted with 1 (0.026 g, 1 mol %) to provide 13 (0.60 g, 65% yield, 85% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.36 (2H, m), 4.05 (2H, t, J=6.8 Hz), 2.05 (3H, s), 2.01 (4H, m), 1.62 (2H, m), 1.27-1.41 (10H, m), 0.90 (3H, t, J=7.4 Hz); 13C NMR (CDCl3): δ 171.2, 129.9, 129.8, 64.7, 29.7, 29.3, 29.2 (2C), 28.6, 27.2, 25.9, 22.9, 21.0, 13.8; HRMS (EI): 227.2021, [C14H26O+H]+ requires 227.2011.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:32][CH:33]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[CH:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:32][CH:33]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(C)(=O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(C)(=O)=O)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 55 (40 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.46 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 7 mg, 19%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].[Br:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O>>[Br:6][C:7]([F:13])([F:14])[C:8]([N:1]([CH2:4][CH3:5])[CH2:2][CH3:3])=[O:10]
Reactant: CCNCC
Reactant: CCOC(=O)C(F)(F)Br
Product: CCN(CC)C(=O)C(F)(F)Br
Reaction time: 1 h

Procedure:
Et2NH (7.9 g, 108 mmol) was added to ethyl bromodifluoroacetate (20.1 g, 99 mmol) at 30° C. The mixture was stirred for 60 min; then all volatiles were removed under reduced pressure. To the residue was added another 7.9 g of Et2NH and the mixture was stirred another 60 min. Again, all volatiles were removed under reduced pressure and the residue (16.3 g, >90% purity by NMR) was used in subsequent steps without further purification.