Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[N:2]1([NH:1][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: NN1CCOCC1
Product: Cn1c(C(=O)NN2CCOCC2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using 4-aminomorpholine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH:22]=[CH:23][C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:24](=[O:25])[CH:23]=[CH:22][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Product: CCOC(=O)c1cc(C(=O)C=Cc2ccc3ccccc3c2)c(C)[nH]1

Procedure:
5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acid ethyl ester (132) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and-3-naphthalen-2-yl-acryloyl chloride following the procedure described in Example 32. Reaction conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 40%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH3:17])=[O:5])[CH3:2].C(Cl)Cl.[Br:21]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[S:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCOCC2)nc1CBr
Yield: 71.2 %

Procedure:
To a round bottom flask containing a solution of ethyl-4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.50 g, 56.57 mmol) in methylene chloride (400 mL, 6000 mmol) were added N-bromosuccinimide (10.07 g, 56.57 mmol) and 2,2′-azo-bis-isobutyronitrile (464 mg, 2.83 mmol). The mixture was stirred at reflux overnight. Reaction was quenched via addition of 10% aqueous sodium bisulfite (20 g in 200 ml water) and stirred for 20 minutes. Mixture was transferred to a separatory funnel, the layers separated, and the aqueous layer was extracted 2×DCM. Combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM and adsorbed onto silica gel. Purification via column chromatography (220 g Isco column, gradient elution 0-10% EtOAc in 1:1 DCM:hexanes) afforded ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (13.5 g, yield 71.1%). LC/MS: (FA) ES+ 335, 337; NMR (300 MHz, CDCl3) δ 4.76 (s, 2H), 4.30 (dd, J=7.1, 7.1, 2H), 3.88-3.72 (m, 4H), 3.62-3.49 (m, 4H), 1.35 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@:6]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])([C:13]([O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[O:14])[C:5](=[O:27])[C:4]=1[C:28]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][C:31]=2[S:30](=[O:44])(=[O:43])[N:29]=1.[CH3:45][O:46][C:47](Cl)=[O:48].C(N(CC)CC)C>ClCCl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@:6]([C:13]([O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:47]([O:46][CH3:45])=[O:48])=[O:14])([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:5](=[O:27])[C:4]=1[C:28]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][C:31]=2[S:30](=[O:44])(=[O:43])[N:29]=1
Reactant: COC(=O)Cl
Reactant: CC(C)CC[C@@]1(C(=O)OC[C@H]2CCCN2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC[C@@H]1COC(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 173 (0.079 mmol) in dry dichloromethane (1 mL) at 0° C. was added methylchloroformate (0.12 mL, 1.55 mmol) and triethylamine (33 μL, 0.24 mmol). The resulting mixture was stirred at rt 3 h and partitioned between H2O (5 mL) and dichloromethane (3× 5 mL). The combined organic layers were dried over Na2SO4, the drying agent was filtered off, and the solvent was removed in vacuo. To a solution of the resulting residue in methanol (1 mL) was added K2CO3, and the resulting mixture was stirred at rt 90 min. The mixture was partitioned between N HCl (5 mL) and ethyl acetate (3× 5 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% methanol in chloroform, and the title compound was obtained as a lt. yellow solid (48 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 0.43 (m, 1H), 0.67 (m, J=6.62 Hz, 3H), 0.71 (d, J=6.62 Hz, 3H), 0.89 (m, 2H), 1.33 (m, 1H), 1.45 (m, 3H), 1.67 (m, 1H), 2.10 (m, 1H), 2.40 (m, 1H), 2.70 (m, 1H), 3.02 (s, 3H), 3.74 (m, 1H), 3.93 (m, 1H), 4.13 (m, 1H), 7.16 (m, 1H), 7.49 (m, 5H), 8.12 (m, 1H), 10.01 (s, 1H), 14.54 (br s, 1H); MS (ESI) m/z=689 [M+H].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]([F:20])=[C:8]([O:21][CH3:22])[N:7]=1)=[CH2:5])C.C(#N)C.C(=O)(O)[O-].[Na+].[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>O>[F:20][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:4](=[O:5])[CH2:3][F:31])=[N:7][C:8]=1[O:21][CH3:22]
Reactant: C=C(OCC)c1nc(OC)c(F)cc1NC(=O)OC(C)(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(C(=O)CF)c(NC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl [2-[1-(ethyloxy)ethenyl]-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (6.72 g, 21.54 mmol), acetonitrile (70 ml), and saturated aqueous sodium bicarbonate solution (15 ml) was treated portionwise over 5 minutes at 0° C. under argon with [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™) (8.9 g, 25.05 mmol). After the addition the mixture was stirred at room temperature for 0.5 hour then treated with saturated aqueous sodium bicarbonate solution (50 ml), stirred for 10 minutes, then diluted with water (100 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed eluting with 0-50% dichloromethane in hexane affording the product as a white solid (3.72 g, 57%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:27]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:29]=1
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 1 (83 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]#[N:15])=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C(=O)C>[C:33]([O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:6]2[C:7]([C:14]#[N:15])=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:19][CH:20]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(=O)CC)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 86.8 %

Procedure:
Following a procedure similar to that described in Example 45(a) but using 0.923 g of 2-butyl-4-propionylimidazole-5-carbonitrile (prepared as described in Preparation 25), 1.56 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 196 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, 1.84 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12]C(F)(F)C(C(F)(F)F)OS(F)(F)F>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][F:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)C(OS(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CF)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A solution of 0.77 g (5 mmol) of 4-nitrobenzyl alcohol in 15 ml of methylene chloride was added dropwise over a period of 10 min to a stirred solution of 2.0 g (7.8 mmol) of 2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfur trifluoride in 5 ml of methylene chloride cooled to 10°. The reaction mixture was warmed to room temperature and then evaporated to dryness under reduced pressure. The residue was recrystallized from pentane to give 0.59 g (76%) of 4-nitrobenzyl fluoride as colorless needles: mp 33° to 34°. Recrystallization from pentane raised to melting point to 36° to 37°.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[C:7]=1[Cl:17])C.[OH-].[K+].O>C(O)C>[Cl:17][C:7]1[C:8]2[C:13](=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2cc(Cl)ccc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of N-(1,6-dichloro-2-naphthyl)carbamic acid ethyl ester (750 mg, 2.64 mmol) and KOH (1.78 mg, 31.7 mmol) in ethanol (20 mL) is heated to reflux temperature under a N2 atmosphere for 12 hours. After cooling to room temperature, water (10 mL) is added. The resulting precipitation is removed by filtration to give 1,6-dichloro-2-aminonaphthalene as a solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[C:6]=1[Cl:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1cc(C(F)(F)F)n[nH]1
Solvent: CN(C)C=O
Product: CCCCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C>[C:35]([NH:38][C:39]1[CH:40]=[CH:41][C:42]([S:45]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:47])=[O:46])=[CH:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 27.6 %

Procedure:
Following the general procedure of Example 11, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 4-(acetylamino)benzenesulfonyl chloride (44 mg, 0.168 mmol) were reacted to give the title compound (20 mg, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18](O)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:5][CH:4]=1.[NH2:26][CH:27]([CH:34]([CH3:36])[CH3:35])[CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]([CH:11]([CH3:12])[CH3:13])[C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([NH:26][CH:27]([CH:28]([OH:33])[C:29]([F:30])([F:31])[F:32])[CH:34]([CH3:35])[CH3:36])=[O:19])=[O:15])=[O:8])=[CH:24][CH:25]=1
Reactant: CC(C)C(N)C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C)cc1

Procedure:
reaction of N-(4-methoxybenzoyl)-L-valyl-L-proline with 3-amino-4methyl-1,1,1-trifluoro-2-pentanol to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro 1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide; followed by
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24](Br)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[C:7]([C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[C:24]1[CH:25]=[C:26]([OH:28])[CH:27]=[C:22]([C:21]([O:20][CH3:19])=[O:30])[CH:23]=1)#[N:8]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of nitrogen, a flask was charged with 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.1 g, 8.2 mmol), 3-bromo-5-hydroxy-benzoic acid methyl ester (1.5 g, 6.2 mmol), potassium phosphate (2.8 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.35 mmol), 1,4-dioxane (90 mL), and water (20 mL). The reaction mixture was stirred at 85° C. overnight. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Yield: 90.9 %

Procedure:
12 g of the product of Step A in 240 cm3 of ethyl acetate were hydrogenated in the presence of 2.4 g of 10% palladium hydroxide on barium sulfate and 2.4 cm3 of quinoline. The mixture was filtered and the filtrate was evaporated to dryness to obtain 11 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[(Z)-2-(methoxy carbonyl)-ethenyl]-cyclopropane carboxylate.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)([CH3:20])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:10]2([CH3:20])[CH:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)=[N:24][CH:25]=1
Reactant: CC1(COc2ccc(Cl)cn2)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(COc2ccc(Cl)cn2)CNCC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To a stirred solution of 2-[(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-ylmethoxy]-5-chloro-pyridine (0.70 g, 1.64 mmol) in toluene (10 mL) at RT was added 1-chloroethyl chloroformate (0.229 mL, 2.12 mmol) and iPr2NEt (0.36 mL, 2.12 mmol). After 3 hours all volatiles were removed under high vacuum and the residue was dissolved in MeOH (10 mL). The reaction mixture was stirred at RT for 2 hours, and then concentrated under high vacuum. Column chromatography (SiO2, CH2Cl2/MeOH, 9:1) afforded 595 mg (97%) of the title product as white foam. ES-MS m/e: 337.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([NH:16][C:17]4[CH:21]=[CH:20][NH:19][N:18]=4)[CH:13]=[C:12]([CH3:22])[N:11]=3)[CH2:9][C@@H:2]12.[C:23](=O)([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:24]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][C:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)[N:15]=[C:10]([N:8]2[CH2:7][C@@H:3]3[C@H:2]([O:1][CH2:6][CH2:5][N:4]3[C:23]([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[O:24])[CH2:9]2)[N:11]=1
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@H]3NCCO[C@@H]3C2)n1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H]3[C@@H](C2)OCCN3C(=O)O[C@@H](C)C(F)(F)F)n1
Temperature: 100 °C

Procedure:
To a mixture of 2-[(4aR,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (3 mL) were added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (37 mg) prepared in Referential Example 2 and DIEA (30 mg) at room temperature. After 4-hour stirring at 100° C. in a sealed tube, the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl (4aR,7aR)-6-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate as a pale yellow foam.
Reaction SMILES: [CH:1]1([N:6]([CH:38]([CH3:40])[CH3:39])[CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([NH:23][CH2:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([O:44][C@H:45]1[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[CH:48](OC(=O)C)[O:47][C@@H:46]1[C:58]1[N:59]=[N:60][N:61]([CH2:63][CH3:64])[N:62]=1)(=[O:43])[CH3:42]>>[C:51]([O:50][C@@H:49]1[C@H:45]([O:44][C:41](=[O:43])[CH3:42])[C@@H:46]([C:58]2[N:59]=[N:60][N:61]([CH2:63][CH3:64])[N:62]=2)[O:47][C@H:48]1[N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([CH2:13][NH:12][C:10]([NH:9][CH2:8][CH2:7][N:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:38]([CH3:40])[CH3:39])=[O:11])=[N:15][C:16]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:53])[CH3:52]
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: CC(C)N(CCNC(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1)C1CCCC1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN(C(C)C)C5CCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared from N-{2-[cyclopentyl(isopropyl)amino]ethyl}-N′-({6-[(2,2-diphenyl-ethyl)amino]-9H-purin-2-yl}methyl)urea (Preparation 44) and (2R,3R,4R)-4,5-bis(acetoxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO 9967265) by a similar procedure to Preparation 26. The title compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CSc1ccc(O)cc1

Procedure:
After 25.42 g of p-hydroxythiophenol was dissolved in 100 ml of methylene chloride, 20.2 g of triethylamine was dropwise added to the solution under ice cooling. Then, 39.2 g of tert-butyl bromoacetate was added to the mixture followed by reacting at room temperature for an hour. After completion of the reaction, the reaction mixture was washed with 3 times with 1N-HCl and once with saturated sodium chloride aqueous solution. After the organic phase was dried over magnesium sulfate, methylene chloride was distilled off to give tert-butyl (4-hydroxyphenylthio)acetate (quantitative).
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][CH:11]=[CH:12][CH:5]2[C:4]1=[O:13].[CH2:14](Cl)[CH3:15]>C(OC)(C)(C)C>[CH2:14]([O:2][N:3]1[C:4](=[O:13])[CH:5]2[CH2:12][CH2:11][CH:10]=[CH:9][CH:6]2[C:7]1=[O:8])[CH3:15]
Reactant: O=C1C2C=CCCC2C(=O)N1O
Reactant: CCCl
Agent: [Na]
Solvent: COC(C)(C)C
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
In an autoclave 60 g of a 20 wt % solution of the sodium salt of N-hydroxytetrahydrophthalimide (0.063 mol), 20 ml of methyl tert-butyl ether and 5.0 g of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was maintained at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction mixture was composed of two liquid layers which were separated. The ether layer was analysed by gas chromatography. A yield of 81% of N-ethoxytetrahydrophthalimide (0.051 mol) was found.