Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2O.FC1C([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:36]1([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:52]([OH:59])(=[O:58])[CH2:53][CH2:54][C:55]([OH:57])=[O:56]>ClCCl.CC(C)=O>[CH:39]1[CH:40]=[CH:41][C:36]([C@@H:42]2[N:43]([C:18]([O:19][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:17])[CH2:44][CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]2=3)=[CH:37][CH:38]=1.[CH2:53]([C:52]([OH:59])=[O:58])[CH2:54][C:55]([OH:57])=[O:56]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: O[C@@H]1CC2CCN1CC2
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C(O)CCC(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution, and then stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 381.5 g (79.4%) of solifenacin succinate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:3]=12.[Cl:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[ClH:20].[CH2:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[C:11]=3[C:2]=2[CH3:1])[CH2:15][CH2:16]1)=[O:22])[CH3:25]
Reactant: Cc1c2c(nc3cccc([N+](=O)[O-])c13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3cccc([N+](=O)[O-])c3c(C)c2CC1
Product: Cl
Yield: 78 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-10-nitro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-10-nitro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH:1]1C[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:8]O.[CH:10]([OH:12])=O>>[C@@H:10]1([OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@H:1]1[OH:8]
Reactant: OO
Reactant: O=CO
Reactant: C1=CCCCCC1
Product: O[C@@H]1CCCCC[C@H]1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Cycloheptene (3.85 g) was added in small portions to 30% hydrogen peroxide (45 mL) and 88% formic acid (180 mL), and the thus-obtained mixture was stirred for 1 hour at 40-50° C., and then at room temperature overnight. The solvent was distilled away under reduced pressure, and to the residue was added 35% aqueous sodium hydroxide, to thereby make the mixture basic. The resultant mixture was stirred at 40-50° C. for 10 minutes, and ethyl acetate was added to the mixture to partition the mixture. The aqueous layer was extracted with ethyl acetate 4 times. The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (4.56 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[OH-].[Na+]>CCO.O>[NH2:30][C:28](=[O:29])[CH2:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH2:25][CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A mixture of 200 mg (0.5 mmol) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 4 mL of 1N NaOH in 10 mL of EtOH was stirred for 1.5 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 5 with 1N HCl, extracted with EtOAc, the EtOAc solution washed with brine and dried (MgSO4). The solvent was evaporated at reduced pressure, the residue stirred with ether/MeOH and the insoluble material filtered to give 120 mg (61% yield) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid, mp, 196-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)c(Br)c1
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A well stirred mixture of commercially available 3-bromo-4-hydroxy-benzaldehyde (40.2 g; 220 mmol), anhydrous K2CO3 (30.4 g; 220 mmol) and commercially available bromomethyl-cyclopropane (32.4 g; 240 mmol) in dry DMF (200 mL) is heated to 60° C. over night. The reaction mixture is filtered, concentrated under reduced pressure, diluted with water and extracted with tert. BuOMe. The combined organic extracts are washed with brine, dried over Mg2SO4 and concentrated under reduced pressure. The residue is chomatographed on silica gel (cyclohexane/AcOEt 100:0 to 85:15) to yield 47.5 g of the title compound as pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@:4]2([CH2:10][CH2:9][C@H:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:7]2)[NH:3]1.[C:21](Cl)(=O)[C:22](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[O:19]=[C:18]1[CH2:22][CH2:21][C:15]2[CH:16]=[C:11]([C@H:8]3[CH2:9][CH2:10][C@@:4]4([NH:3][C:2](=[O:1])[O:6][CH2:5]4)[CH2:7]3)[CH:12]=[CH:13][C:14]=2[CH2:17]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a mixture of 2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetic acid (I-5B, 800 mg, 2.91 mmol) in DCM (20 mL) was added oxalyl chloride (1 ml, 11.42 mmol) and a few drops of DMF. After one hour, the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (20 mL) in a glass pressure vessel. Granular aluminum chloride (1550 mg, 11.62 mmol) was added and the reaction mixture was cooled to −78° C. Ethylene was bubbled through the solution for 5 minutes and then the reaction vessel was sealed. The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours. The mixture was poured onto ice, diluted with dichloromethane and washed with 1M HCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (80 g) using a MeOH/DCM gradient (0-10% MeOH over 13 CV). The product containing fractions were collected and dried in vacuo to afford 770 mg of (5R,7S)-7-(6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one. HPLC retention time=0.74 min (Condition G); LC/MS M+1=286: 1H NMR (400 MHz, chloroform-d) δ 7.20-7.00 (m, 3H), 5.49 (br. s., 1H), 4.45-4.25 (m, 2H), 3.59 (s, 2H), 3.08 (t, J=6.8 Hz, 3H), 2.58 (t, J=6.7 Hz, 2H), 2.38 (dd, J=13.2, 7.3 Hz, 1H), 2.27-2.11 (m, 2H), 2.05-1.92 (m, 2H), 1.92-1.74 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[O:6][C:7]([F:15])([F:14])[CH2:8][O:9][CH2:10][CH2:11][CH2:12]Cl.BrCCCCl.[CH2:27]([O:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:27]([O:33][C:34]1[CH:39]=[N:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:12][CH2:11][CH2:10][O:9][CH2:8][C:7]([O:6][C:5]([F:17])([F:16])[C:4]([F:19])([F:18])[O:3][C:2]([F:21])([F:20])[F:1])([F:15])[F:14])=[CH:44][CH:45]=2)=[N:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCl
Agent: ClCCCBr
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (4.5 g, 11.7 mmol; prepared by combining 1-bromo-3-chloropropane with 3-(2-(2-(trifluoromethoxy) tetrafluoroethoxy)-2,2-difluoroethanol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol). The resulting product was isolated by addition of water (50 mL) to the reaction mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 180°-183° C. at 0.1 torr; yield of 3.9 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.O>ClCCl>[N:26]1([C:32]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:8][CH:7]=3)[CH2:10][CH:11]([NH:15][C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:23])[CH2:12]2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., 705 mg (2.02 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 70 ml of dichloromethane, and 321 mg (2.02 mmol) of morpholine-4-carbonyl chloride and 564 μl (4.04 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 960 mg (100% of theory)
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH4+:18].[OH-]>CS(C)=O.CCOC(C)=O>[NH2:18][C:2]([CH3:1])([CH2:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)/C(C)=C/C(=O)c1ccc(C)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(N)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of Intermediate 102A (1.067 g, 4.59 mmol) in DMSO (20 mL) under argon was added NH4OH (18.04 mL, 271 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (40 mL) and brine (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (120 g silica gel) to provide the desired product (0.632 g, 55%) as a clear oil. LCMS Anal. Calc'd for C14H19NO3 249.14, found [M+H] 250.1. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz, 1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s, 3H), 1.19 (t, J=7.01 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C.O1CCOCC1.ClCCl>[CH2:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([N:1]1[C:24]2[CH:4]=[CH:3][CH:2]=[CH:18][C:28]=2[C:27]2[C:26]1=[CH:27][CH:28]=[CH:24][CH:26]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 49.5 %

Procedure:
A vigorously stiffed solution of L-Lys(Z)—OMe (3.31 g, 10 mmol) in acetic acid (20 mL) and dioxane (40 mL) was heated to 75° C., at this temperature 2,5-dimethoxytetrahydrofuran (DMTHF, ee 97%) (3.97 g, 3.90 mL, 30 mmol) was added dropwise to the reaction mixture. After complete addition of DMTHF, the reaction mixture was refluxed at 110° C. for 3 h followed by 5-6 h stiffing at room temperature. The volatiles were removed under reduced pressure to afford a dark brown residue, which was dissolved in dichloromethane (100 mL) and washed with 10% NaHCO3 solution (15 mL), brine (15 mL) and water (15 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 mesh) using hexane:ethyl acetate (7:3) as eluent to afford (S)-methyl 6-benzyloxycarbonylamino-2-carbazol-9-yl-hexanoate 3 (1.10 g, 25%) as a pale yellow solid.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[S:20][C:21]([C:25](=[O:34])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([CH3:24])[N:23]=2)[C:15](=[O:35])[CH:14]=1)(=O)=O>>[CH2:27]([NH:26][C:25]([C:21]1[S:20][C:19]([N:16]2[CH:17]=[CH:18][C:13]([CH:1]3[CH2:3][CH2:2]3)=[CH:14][C:15]2=[O:35])=[N:23][C:22]=1[CH3:24])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1nc(-n2ccc(OS(=O)(=O)C(F)(F)F)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: OB(O)C1CC1
Product: Cc1nc(-n2ccc(C3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 54 %

Procedure:
Following the procedure as described in Example 19, making variations only as required to use cyclopropylboronic acid in place of phenethylboronic acid to react with -(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate, the title compound was obtained as a colorless solid in 54% yield: mp 149-151° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=7.6 Hz, 1H), 7.39-7.25 (m, 5H), 6.39 (d, J=1.5 Hz, 1H), 6.10-6.05 (m, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.69 (s, 3H), 1.81-1.72 (m, 1H), 1.14-1.07 (m, 2H), 0.86-0.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.2, 160.3, 158.8, 153.4, 152.3, 137.7, 130.3, 128.8, 127.9, 127.6, 127.7, 114.7, 106.6, 44.1, 17.3, 15.4, 10.4; MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[O:53][CH2:52]C1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH:23]2[CH2:52][OH:53])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1COCCN1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and morpholin-3-ylmethanol and isolated as light-yellow gum (13.3 mg, 68%). MS (m/e): 417.4 (MH+).
Reaction SMILES: C([NH:4]C(C)C)(C)C.[N:8]1([C:13]2[N:18]=[C:17]([CH2:19]N=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37].Cl>C1COCC1>[CH2:40]([O:39][C:35](=[O:38])[CH:36]([NH2:4])[CH2:37][CH2:19][C:17]1[CH:16]=[C:15]([CH3:34])[N:14]=[C:13]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:18]=1)[CH3:41]
Reactant: CC(C)NC(C)C
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(CN=C(c2ccccc2)c2ccccc2)nc(-n2ccnc2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(N)CCc1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 134.3 %

Procedure:
nButyllithium (1.50 mL of a 2.82 M solution in hexanes, 4.23 mmol) was added dropwise over 10 minutes to a solution of diisopropylamine (370 mg, 3.66 mmol) and anhydrous THF (10 mL) at 0° C. under an atmosphere of N2. The mixture was stirred for 10 minutes then cannulated into a −45° C. solution of (2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-(diphenylmethylene)methanamine (1.00 g, 2.83 mmol) and anhydrous THF (10 mL) under a N2 atmosphere. The reaction mixture was stirred for 30 minutes then ethyl acrylate (341 mg, 3.41 mmol) was added dropwise over 10 minutes. The reaction mixture was warmed to rt then stirred for 12 h. The mixture was cooled to 0° C. then HCl (50 ml, 10% v/v aqueous) was added dropwise over 15 minutes. The solution was warmed to rt, extracted with ethyl ether (3×30 mL), and the aqueous layer was adjusted to pH=8.5 with solid K2CO3. The resulting solution was extracted with DCM (3×30 mL), combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford 1.10 g of amino-4-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-butyric acid ethyl ester as a brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[H-].[Na+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>CN(C=O)C.O>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:26]2[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: Clc1nc2ccccc2s1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(Oc2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (E)-N-methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetamide (0.21 g) in DMF (3 ml), sodium hydride (34 mg) and 2-chloro-1,3-benzothiazole (0.18 g) were added, and the resultant mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether. The solvent was dried and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:28][NH2:29].C(O)(=O)C>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[NH:29][N:28]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)[nH]n2)cc1
Yield: 78 %

Procedure:
190 mg (0.54 mmol) methyl 4-[3-(4-butoxyphenyl)-3-oxopropanoyl]benzoate was dissolved in 10 mL ethanol and 0.5 mL hydrazine hydrate and 1 mL acetic acid were added. The mixture was refluxed for 1 h. Upon cooling, the product crystallized. To complete crystallisation, 5 mL water was added and the product was filtered off, washed with water and dried. A white crystalline material (150 mg, 0.42 mmol, 78%) was isolated and directly used for the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH:15]([CH:16]=[CH2:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH:15]([CH:16]=[CH2:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: C=CC1C(CO)C1C(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CC1C(C=O)C1C(=O)OCC
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of oxalyl chloride (0.30 mL, 3.5 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under nitrogen atmosphere, dimethylsulfoxide (0.51 mL, 7.2 mmol) was added and stirred for 30 minutes. To this mixture, a solution of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-vinylcyclopropane carboxylate (490 mg, 2.9 mmol) in anhydrous dichloromethane (20 mL) was added and reaction stirred at the same temperature for 45 minutes. Then, triethylamine (2.0 mL, 14.4 mmol) was added and mixture was allowed to react at room temperature. After 30 minutes, the reaction was quenched with water (30 mL), the layers were separated and the aqueous one was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by column chromatography using ethyl acetate and hexane 1:4 as eluent to afford 460 mg (95% yield) of ethyl (1SR,2SR,3RS)-2-formyl-3-vinylcyclopropane carboxylate.