Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>CCOC(C)=O.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.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: FC(F)(F)c1ccc(Br)nc1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A stirred mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (300 mg, 0.95 mmol; see step (a)), 2-bromo-5-(trifluoromethyl)pyridine (323 mg, 1.43 mmol), sodium carbonate (2M, 1.43 mL, 2.85 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80° C. for 2 h. Another portion of Pd(PPh3)4 (54 mg, 0.05 mmol) was added and the heating continued for 16 h. The mixture was diluted with EtOAc, washed with brine, dried over MgSO4, concentrated and purified by chromatography to give the sub-title compound (247 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1.[OH-].[NH4+:18]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:18])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: [NH4+]
Reactant: CN(C)CCn1cc(Br)c2c(Cl)ncnc21
Agent: [OH-]
Product: CN(C)CCn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Yield: 116.1 %

Procedure:
To [2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]dimethylamine (175 mg, 0.576 mmol) was added ammonium hydroxide (22.45 μl, 0.576 mmol) in to a 5 ml sealable vial. The vial was then capped and heated at 100° C. overnight. The reaction was cooled to room temperature and concentrated to a light brown oil of 5-bromo-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (190 mg, 0.669 mmol, 116% yield), which was used without further purification. LC/MS (ES) m/z=284.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ8.14 (s, 1H), 7.53 (s, 1H), 6.82 (br. s., 2H), 4.48 (t, J=6.32 Hz, 2H), 3.41 (br. s., 2H), 2.71 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: N#Cc1cccc(N)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00 g, 9.01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37 mmol), then solid NaBH(OAc)3 (2.48 g, 11.7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, then dried over MgSO4, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1.58 g (54%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]benzonitrile product as a clear oil. 1H NMR (CDCl3) δ 4.38 (s, 3H), 5.89 (dt, 1H), 6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7]C(C)(C)C)=[O:6].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)O)ccc1Oc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
A mixture of tert-butyl 3-methyl-4-phenoxybenzoate (654 mg, 2.3 mmol), 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were stirred at 20° C. for 4 hours. The mixture was washed with water (10 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 3-methyl-4-phenoxybenzoic acid as a white solid (200 mg, 38%). LRMS (M+H)− m/z: calcd 228.08. found 228.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:19](=[O:20])[N:18]([CH3:17])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N(C)C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 74.1 %

Procedure:
Into 80 ml of dichloromethane, were dissolved 10.8 g of 1-(p-fluorophenyl)piperazine and 6.1 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 10.0 g of 2,4,4-trimethylallophanoyl chloride. After one hour of reaction at room temperature, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and ether to obtain 13.7 g (74% yield) of 1-(p-fluorophenyl)-4-(2,4,4-trimethylallophanoyl)piperazine having a melting point of 83°-84° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][C:11]1=[O:12].C(NC1C=CN([C@@H]2O[C@H](CO[C:46]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C@@H](O)C2)C(=O)N=1)(=O)C1C=CC=CC=1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([C:46]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][C:11]3=[O:12])[C@@H:2]([F:1])[C@@H:6]2[OH:7])([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[CH:60][CH:59]=1
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1)c1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared from 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-N4 -benzoylcytosine by the same procedure used for the preparation of N4 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(CC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidine-1-carboxylate (Intermediate 234, 0.55 g) in DCM (5 mL) and the mixture was stirred at room temperature for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in a small amount of methanol and loaded onto a 20 g SCX-2 SPE cartridge, washed with methanol then eluted with 2M ammonia in methanol to give (R)-2-[2-(3-fluorophenyl)-ethyl]pyrrolidine (0.39 g).
Reaction SMILES: [Cl:1][C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH2:19]CO)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH2:19][CH2:5][O:4][C:2]([Cl:1])=[O:3])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(CCO)c([N+](=O)[O-])cc1OC
Solvent: C1CCOC1
Product: COc1cc(CCOC(=O)Cl)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Trichloromethyl chloroformate (0.26 ml, 2.2 mmol) in THF (5 ml, dist. over CaH2) was cooled by means of an ice bath to 0° C. A solution of 2-(4,5-dimethoxy-2-nitrophenyl)ethanol (500 mg, 2.2 mmol) and Et3 N (218 mg, 0.3 ml, 2.2 mmol, dist. over CaH2) in THF (15 ml, dist. over CaH2) was added dropwise thereto for 10 min. The ice bath was then removed and the solution was stirred further at room temperature. After being stirred for 30 min, a spatula tip of activated carbon was added to the reaction mixture, which after being stirred for another 2.5 h was filtered by suction at room temperature over Celite. The solvent and the excess reagent were removed from the filtrate by distillation in a high vacuum and 2-(4,5-dimethoxy-2-nitrophenyl)ethoxycarbonyl chloride (624 mg, 98%) was obtained as a yellow brown solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 85.9 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 4-[(tert-butoxycarbonylamino)methyl]phenylboronic acid (180 mg, 0.73 mmol) to afford the desired product (180 mg, 83%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=3)=[CH:9][CH:8]=[C:7]([F:31])[C:3]=1[C:4]([NH2:6])=[O:5].[C:32]1(OS(C(F)(F)F)(=O)=O)[CH2:36][CH2:35][CH2:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH:36]1([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]([CH2:12][O:11][C:10]2[C:2]([F:1])=[C:3]([C:7]([F:31])=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])=[CH:21]3)[CH2:35][CH2:34][CH:33]=[CH:32]1
Reactant: CC1(C)OB(c2ccc3c(c2)C=C(COc2ccc(F)c(C(N)=O)c2F)C3)OC1(C)C
Reactant: O=S(=O)(OC1=CCCC1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4C=CCC4)ccc3C2)c1F
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.25 g, 0.56 mmol) in 7 ml of anhydrous DMF and water (3.5 ml) was added trifluoromethanesulfonic acid cyclopent-1-enyl ester (0.37 g, 1.70 mmol) and potassium phosphate (0.14 g, 0.60 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.05 g, 0.08 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.14 g, 65%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.22 (m, 2H), 2.01 (m, 2H), 2.88 (m, 2H), 5.68 (s, 2H), 6.43 (s, 1H), 7.01 (t, J=9.20 Hz, 1H), 7.37 (m, 1H), 7.67 (d, J=8.40 Hz, 1H), 7.89 (br s, 1H), 7.94 (s, 1H), 8.07 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (387.15), HPLC (method II) Rt=13.74 min.
Reaction SMILES: [CH2:1]([N:5]([C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[CH:18]([CH3:20])[CH3:19])[C:6](=O)[CH3:7])[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:1]([N:5]([CH2:6][CH3:7])[C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[CH:18]([CH3:20])[CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(C)=O)c1c(C(C)C)nc2ccccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN(CC)c1c(C(C)C)nc2ccccn12

Procedure:
N-butyl-N-(2-isopropylimidazo[1,2-a]pyridin-3-yl)acetamide 16 (287 mg, 1.05 mmol) was reacted with LiAlH4 (2 eq., 2.10 mmol, 80 mg) in THF (10 ml) at room temperature. Progress of the reaction was monitored by TLC. Aqueous NaOH solution was used to quench the reaction. Solids were filtered and washed with ethyl acetate and the product was purified by column chromatography, eluting with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(-c2nc3c(O)cccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc3c(OC(C)=O)cccc3s2)cc1

Procedure:
The 4-hydroxy-2-(4-methoxyphenyl)benzothiazole (4.0 g) obtained in Example 2 was added to 40 ml of acetic anhydride, and the mixture was refluxed for 1 hour. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane and ethyl acetate to give 4.0 g of 4-acetoxy-2-(4-methoxyphenyl)benzothiazole.
Reaction SMILES: C(O[C:6]([N:8]([CH3:12])[N:9](C)[CH3:10])=O)(C)(C)C.[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[CH3:6][N:8]([CH3:12])[NH:9][CH3:10]
Reactant: CN(C)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNN(C)C
Reaction time: 1 h

Procedure:
To a solution of N,N',N'-trimethylhydrazinecarboxylic acid tert-butyl ester (0.52 g, 2.99 mmol) in methylene chloride (4 ml) was added trifluoroacetic acid (4 ml) and the mixture was stirred for 60 min. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.61 g of N,N,N'-trimethylhydrazine trifluoroacetate as a thin oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Si:10]([O:2][CH2:1][CH2:3][NH2:4])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
Ethanolamine (2.00 g, 32.7 mmol) was dissolved in DMF (15 mL) followed by addition of imidazole (1.11 g, 16.4 mmol) and tert-butyldimethylsilyl chloride (2.46 g, 16.4 mmol), and then the mixture was stirred at room temperature for 12 hours. Water and an aqueous saturated sodium hydrogencarbonate solution were added to the reaction mixture in that order, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give 2-(tert-butyldimethylsilyloxy)ethylamine (1.59 g; yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][C:12]1([F:15])[F:14])[OH:10].[C:16](OC(C1CC1(F)F)C1C=CC(C(F)(F)F)=CC=1)(=[O:18])[CH3:17]>>[C:16]([O:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH:11]1[CH2:13][C:12]1([F:15])[F:14])(=[O:18])[CH3:17]
Reactant: OC(c1ccc(Cl)cc1Cl)C1CC1(F)F
Reactant: CC(=O)OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Product: CC(=O)OC(c1ccc(Cl)cc1Cl)C1CC1(F)F

Procedure:
The title compound was prepared starting from 8.20 g (32.4 mmol) of a mixture of the two diastereomers of the compound from Example 191A in analogy to the synthesis of the compound from Example 192A. 7.70 g (81% of theory) of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:21][O:22][CH3:23])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: COCCl
Reactant: COc1cccc(C=O)c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Hydroxy-3-methoxybenzaldehyde (90 mg, 0.59 mmol) was placed in a 20 mL reaction vessel, and dissolved in 1.8 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), 4-dimethylaminopyridine (9 mg, 0.07 mmol), and chloromethyl methyl ether (112 μL, 1.48 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 30 mL of ethyl acetate and 7 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (93.4 mg, 80%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:8][N:9]=1)[C:2]#[CH:3].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:4][C:5]1[S:6][C:7]([CH2:10][CH:11]([C:12]#[N:13])[C:14]#[N:15])=[CH:8][N:9]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ncc(C=C(C#N)C#N)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCOc1ncc(CC(C#N)C#N)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Then, the resulting {[2-(2-propynyloxy)-1,3-thiazol-5-yl]methylidene}malononitrile was dissolved in 20 ml of ethanol, and a suspension of 0.09 g of sodium borohydride in 1 ml of ethanol was added dropwise. The mixture was stirred at room temperature for 1 hour. After 10 ml of 3% hydrochloric acid was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.55 g of {[2-(2-propynyloxy)-1,3-thiazol-5-yl]methyl}.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4](S)[N:3]=1.ClCC(O)=[O:16].Cl>O>[CH:9]([O:8][C:7]1[C:2](=[O:1])[NH:3][C:4](=[O:16])[NH:5][CH:6]=1)([CH3:11])[CH3:10]
Reactant: O=C(O)CCl
Reactant: CC(C)Oc1cnc(S)nc1O
Agent: Cl
Solvent: O
Product: CC(C)Oc1c[nH]c(=O)[nH]c1=O

Procedure:
60.8 g of 4-hydroxy-5-isopropoxy-2-mercapto-pyrimidine are refluxed together with 60 g of chloroacetic acid in 1.2 litres of water for 2.5 hours, during which time the precipitate dissolves completely. 200 ml of conc. hydrochloric acid are added and the mixture is refluxed for a further 7 hours. Then the reaction mixture is evaporated down to 500 ml, whereupon the desired product is obtained as a precipitate, filtered off and dried overnight at 70° C. (28.6 g; 52%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([N+:16]([O-])=O)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1.[H][H]>C(O)C.[Pd]>[NH2:16][C:8]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[O:3][C:2]([CH3:19])([CH3:1])[CH2:6][C:5]=2[CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution ethyl 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate (674) (1.02 g, 3.84 mmol) in ethanol (40 mL) was added Pd/C (100 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (675) (899 mg, 99%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.CN(C)O.CN([C:35]([O:39][N:40]1N=NC2C=CC=C[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:14](=[O:16])[N:40]([O:39][CH3:35])[CH3:41])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-tert-butoxycarbonyl-N-methyl-L-leucine (5.0 g, 20.4 mmol) was dissolved in DMF (100 mL), treated with treated with N,N-diisopropylethylamine (28 mL, 163 mmol), N,N-dimethylhydroxylamine hydrochloride salt (2.0 g, 20.4 mmol), and HBTU (7.73 g, 20.4 mmol), then stirred overnight at room temperature. The reaction was diluted with EtOAc (500 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give the desired product as an oil; MS: 289.2 (M+1 for C14H28N2O4); TLC (SiO2) Rf 0.39 (8% MeOH/CH2Cl2), visualized with ninhydrin.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>C1COCC1.O1CCOCC1>[ClH:37].[ClH:37].[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2 g, 3.9 mmol) in 10 mL of THF was added 10 mL of 4 N HCl in dioxane. The solution was stirred at room temperature for 1 hour and concentrated in vacuo to provide 1.9 g (99%) of the title compound as a white powder solid, which was used for the next reaction without purification. LC-MS: [M+H]+=410.3.