Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1)=[C:5]=[O:6]>C(#N)C>[CH3:1][N:2]([CH3:3])[C:5]([NH:4][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1)=[O:6]
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
5 parts of gaseous dimethylamine were passed into a solution of 33.6 parts of 5-(4'-isocyanato-2'-trifluoromethylphenoxy)-benzisothiazole in 400 parts of acetonitrile at from 10° to 20° C. and the reaction was allowed to continue for 12 hours at from 20° to 30° C., after which the solvent was removed under reduced pressure and the residue was recrystallized from chloroform. 32.7 parts (86% of theory) of 5-(4'-dimethylaminocarbonylamino-2'-trifluoromethylphenoxy)-benzisothiazole of melting point 188° C. were obtained.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]3=O.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][N:25]=[C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]4[N:3]=[CH:2][S:1][C:5]4=3)[NH:9][C:8]2=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Reactant: COc1cccc(NN)c1
Agent: Cl
Product: COc1cccc(NN=C2C(=O)Nc3ccc4ncsc4c32)c1
Yield: 44 %

Procedure:
Prepared according to Procedure H using 6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (Procedure A) and 3-methoxyphenylhydrazine hydrochloride in 44% yield. APCI-MS m/z 323 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N:23]1([C:29]([CH2:31][CH2:32][C:33](O)=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:23]1([C:29]([CH2:31][CH2:32][C:33]([O:8][C:7]2[CH:6]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])[C:4]([F:22])=[CH:3][C:2]=2[Cl:1])=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=C(O)CCC(=O)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)CCC(=O)N3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 3-[piperidino(carbonyl)]-propionic acid with N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as the catalyst in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenyl 3-[piperidino(carbonyl)]propionate. 1H-NMR (CDC3, 400 MHz): 7.35 ppm (d,1H), 7.20 ppm (d,1H), 6.36 ppm (s,1H), 3.50-3.60 ppm (m,5H), 3.42 ppm (t,2H). 2.94 ppm (t,2H), 2.74 ppm (t,2H), 1.49°-1.70 ppm (m.6H);
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([C:11]([O:13]CC)=[O:12])[CH2:10][CH2:9]1)=[O:7])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1 N NaOH (275 mL, 275 mmol) was added under nitrogen dropwise to a solution of 1,1-cyclopropanedicarboxylic acid diethyl ester (51.3121 g, 275 mmol) in 400 mL of absolute ethanol at room temperature. After the addition, the reaction was allowed to stir at room temperature overnight. The reaction was concentrated under reduced pressure to remove most of the ethanol. The residue was partitioned between water and ether. The aqueous layer was separated, extracted with ether, acidified with 2 N HCl and extracted four times with ether. The combined extracts were dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give a yellow oil. The oil was dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 1,1-cyclopropanedicarboxylic acid monoethyl ester (39.8275 g, 91%) as a yellow oil.
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:29])([CH3:28])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:26][OH:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].[C:30]1([C:38](OCC)=[O:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH2:36]([O:35][C:33]([C:30]1([C:38]2([OH:39])[O:27][N:26]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][Si:10]([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:29])[CH3:28])=[CH:13][CH:14]=3)[CH:19]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in hexane, 983.8 mL) is added to a solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone oxime, which may be produced as in Example 136 (400 g) in THF (4 L) at 0° C. and the reaction solution is stirred for one hour at this temperature. Diethyl 1,1-cyclopropanedicarboxylate (227 mL) is added to the reaction solution, stirred for one hour at 0° C. and then the reaction is quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure. The crude product is purified by column chromatography with 5-10% ethyl acetate in hexane to give a light yellow solid, which is triturated with pentane and filtered to give 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-hydroxy-4-phenyl-4,5-dihydro-isoxazol-5-yl}-cyclopropanecarboxylic acid ethyl ester (230.8 g.)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:28][CH3:29])=[C:11]([CH:27]=1)[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=1[CH2:22][S:23][CH:24]([CH3:26])[CH3:25])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:36]([NH2:38])[CH3:37].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:38][CH2:36][CH3:37])=[CH:15][C:14]=2[CH2:22][S:23][CH:24]([CH3:26])[CH3:25])[CH:27]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)O)cc2CSC(C)C)c1
Reactant: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(Oc2cc(CC(=O)OCC)ccc2OC)c(CSC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid (0.07 g, 0.17 mmol) in CH2Cl2 (10 mL) and DMF (1 drop) was added oxalyl chloride (0.04 mL, 0.5 mmol), and the reaction was stirred at room temperature for 30 minutes. After concentrating to dryness, ethylamine (2M in THF; 0.25 mL, 0.5 mmol) was added, followed by CH2Cl2 (10 mL) and diisopropylethylamine (0.5 mL), and the reaction was stirred at room temperature for 15 minutes. The mixture was worked up to give the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=O)=[CH:10][CH:9]=1)([O-:7])=[O:6].[BH4-].[Na+].O>C1(C)C=CC=CC=1.CO.ClCCl>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][NH:3][CH2:2][CH2:1][NH2:4])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=CCCc1ccc([N+](=O)[O-])cc1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NCCNCCCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Add ethylene diamine (200 mL, 3000 mmol) and toluene (1200 mL) to a 3 L flask and cool to <5° C. Add a solution of 3-(4-Nitro-phenyl)-propionaldehyde (63 g, 280 mmol) in toluene (300 mL) via addition funnel over 45 minutes with vigorous stirring. Remove the cooling bath and heat to reflux to remove water by azeotropic distillation (Dean Stark trap). Concentrate the reaction under reduced pressure to an oil. Dilute the crude oil with methanol (450 mL) and cool to 0° C. Add sodium borohydride (13 g, 340 mmol) in 1-2 g portions with stirring, holding the temperature below 5° C. Stir the reaction for 20 minutes at 5° C. and then allow the reaction to warm to room temperature and stir for an additional 30 minutes. Cool to <0° C. and add water and dichloromethane. Separate the layers and extract the aqueous layer with dichloromethane. Combine the organic layers and wash with brine and dry over MgSO4. Filter the slurry and concentrate under reduced pressure to a red oil (73 g). The title compound was used without purification. 1H NMR (CDCl3, 500.0 MHz): δ 8.12 (d, 2H, J=8 Hz), 7.32 (d, 2H, J=8 Hz), 2.74-2.81 (m, 4H), 2.61-2.67 (m, 4H), 1.84 (p, 2H, J=7.5 Hz), 1.57 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].C(N(CC)CC)C.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl.O>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH3:14])=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (commercially available, for example from Sunshine Chemlab, Downington, Pa., USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). The organics were combined, passed through a phase separator and concentrated to afford 710 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21][OH:22])=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CO)cnc21
Yield: 89.2 %

Procedure:
4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (289 mg, 0.620 mmol) in methanol was stirred with sodium borohydride (35.3 mg, 0.93 mmol) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (258 mg, yield 89%).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13](I)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:28]4[CH:27]=[CH:26][C:25]([CH2:24][N:21]5[CH2:20][CH2:19][CH:18]([O:17][CH3:16])[CH2:23][CH2:22]5)=[CH:30][CH:29]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 85 °C
Yield: 28.1 %

Procedure:
A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.50 g, 1.3 mmol), 4-methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine (0.80 g, 2.4 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.16 g, 0.2 mmol) in 2-methyl THF (20 mL) and saturated aqueous sodium carbonate (10 mL) was heated at 85° C. for 3 h. The material was partitioned between DCM, water and methanol and the phases were separated. The organic phase was separated, dried over sodium sulfate, filtered and evaporated to afford a residue which was purified by flash chromatography (silica, 50 g column, Biotage, 0-10% methanol in DCM). The resultant material was triturated with methanol to afford the title compound as a tan solid (0.165 g, 28%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.84 (d, J=2.2 Hz, 1H), 8.73 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.30 (d, J=1.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, H), 2.89-2.76 (m, 2H), 2.37-2.22 (m, 2H), 2.02-1.89 (m, 2H), 1.73-1.56 (m, 2H). LCMS (Method G): RT=3.30 min, M+H+=451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=[CH:18][CH:19]=1)[C:5]([CH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9](=[O:16])[O:8]1)=O.[OH-:20].[Na+].Cl.O>CO.O1CCCC1>[OH:20][CH2:18][C:19]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:7]=1[C:11]1[C:10]([C:9]([OH:8])=[O:16])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C1OC(C(=O)c2cccc(Cl)c2)c2ncccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1-c1cccc(Cl)c1CO
Temperature: 75 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
7-(3-Chlorobenzoyl)-furo[3,4-b]pyridin-5-one (4.77 g, 19.4 mmoles) and 0.2N sodium hydroxide (21.4 mmoles) was dissolved in methanol and tetrahydrofuran (100 ml, 1:1). The mixture was heated to 75° C. and stirred for 3 hours and cooled. 1N Hydrochloric acid (20 ml) and water (200 ml) was added to the mixture. The resulting solution was extracted with ethyl acetate and dried over Na2SO4. The solution was filtered and the solvent removed yielding 4.94 g (96.8%) of 2-(hydroxymethyl-3-chlorophenyl)-3-carboxypyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:25]3[C:24]([F:23])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Reactant: CSc1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1
Product: Fc1ccc(-c2cnnc(-c3ncccc3F)n2)cc1-c1ncccc1F
Yield: 12 %

Procedure:
5-[4-Fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine (100 mg, 0.32 mmol) was coupled to 3-fluoro-2-tributylstannylpyridine (146 mg, 0.38 mmol) using the method described in Example 36 to give 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(3-fluoropyridin-2-yl)-[1,2,4]triazine as a yellow solid (14 mg): δH (400 MHz, CDCl3) 7.38-7.46 (2H, m), 7.52-7.60 (2H, m), 7.64-7.70 (1H, m), 8.44-8.48 (1H, m), 8.54 (1H, dd, J 2.3, 6.7 Hz), 8.59-8.61 (1H, m), 8.71 (1H, d, J 4.3 Hz), 9.79 (1H, s); m/z (ES+) 366.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22].[Cl-].[Na+]>O1CCCC1.[Cu]I.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([C:21]#[C:22][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: Brc1cccc(-c2ncccn2)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc(-c2ncccn2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.00 g (3.99 mmol) of 2-(6-bromopyridin-2-yl)pyrimidine, 45.5 mg (239 μmol) of copper(I) iodide and 670 μl (4.78 mmol) of N-isopropylpropane-2-amine were initially charged in 15 ml of tetrahydrofuran and degassed in an ultrasonic bath under argon. The reaction mixture was then heated to 50° C., 168 mg (239 mol) of dichloro[bis(triphenylphosphoranyl)]palladium were added and 1.70 ml (12.0 mmol) of ethynyl(trimethyl)silane were added dropwise over a period of one hour. The mixture was then stirred at 60° C. for a further two hours. For work-up, the mixture was added to semiconcentrated sodium chloride solution, the mixture was filtered through Celite and the aqueous phase was extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, concentrated and purified chromatographically. This gave 520 mg (51% of theory) of 2-{6-[(trimethylsilyl)ethynyl]pyridin-2-yl}pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=1)[CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)C.[OH-].[Na+]>C(O)C>[C:4]([CH2:5][N:6]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:29][CH:30]=1)[CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)([OH:31])=[O:3]
Reactant: CCOC(=O)CN(Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN(CC(=O)O)Cc2ccco2)cc1
Yield: 74 %

Procedure:
22.01 g (51.00 mmol) of the compound from Example III-15 are stirred at 80° C. in 785 ml of ethanol in the presence of 6.12 g (153.00 mmol) of sodium hydroxide for 1 hour. The solvent is distilled off and water is added, and the mixture is then acidified using 1 N hydrochloric acid and extracted with ethyl acetate. The extract is then washed with water and saturated sodium chloride solution and dried over magnesium sulphate. The amount of solvent is reduced and the product is then filtered off with suction and dried, giving the target compound in a yield of 74%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27][N:32]2[CH2:33][CH2:34][N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(benzyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=O)[CH2:3]1.BrCC1CC1>>[NH:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CC(=O)Nc2ccccc2N1
Agent: BrCC1CC1
Product: c1ccc2c(c1)NCCCN2

Procedure:
2,4-Dioxo-1,5-bis-cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A, and (bromomethyl)cyclopropane (Lancaster). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to straight EtOAc), then recrystallization from EtOAc/hexanes.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:33][CH3:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].Cl>C(#N)C.O.[Li+].[OH-]>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:33][CH3:34])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoate ((0.308 g, 0.64 mmol) in acetonitrile (32 mL) was added aqueous 0.10 M LiOH (16 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 0.10 M LiOH (to a total volume of 100 mL, pH˜10) and washed with diethyl ether (2×100 mL). The aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with 5% HCl (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.279 g (96%) of a colourless oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][C:24]2[N:35]([CH3:38])[N:36]=[CH:37][C:23]1=2)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:25][C:24]2[N:35]([CH3:38])[N:36]=[CH:37][C:23]1=2)=[O:19]
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 13 h
Yield: 94.5 %

Procedure:
A mixture of tert-butyl 4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 138 (0.42 g, 0.80 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at one atm. at room temperature for 13 h. The mixture was filtered through Celite pad and concentrated to give a residue which was subjected to chromatography to provide 139 (0.33 g, 94%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:20])=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10]=1[CH:11]=O)=[O:5])[CH3:2].[CH2:21]([O:23][C:24]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH3:22]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:20])=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10]=1[CH:11]=[CH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c(C=O)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 b (23 g, 81.7 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (34.66 g, 99.4 mmol) were dissolved in 450 ml of tetrahydrofuran, and stirred at room temperature overnight under an argon atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain a yellow oil. The residue was dissolved in the solvent mixture of n-hexane and ethyl acetate (V:V=20:1), and purified by sand funnel decompression column chromatography to obtain the title compound 5-(2-ethoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1c (24 g, yield 84%) as a light yellow solid.