Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:34][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:16][CH3:17])([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)C)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)C)ccc2o1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid dimethylamide (45 mg, 0.0972) in THF (5.0 mL) at RT is treated with NaBH4 (7 mg, 0.194 mmol). The resulting mixture is stirred for 1 hour. The reaction is quenched with water (1.0 mL) and extracted with EtOAc (2×20 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (20% EtOAc/Hex) to afford the title compound (45 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: BrCc1ccccc1
Product: Clc1nc(N2CCOCC2)c2ncn(Cc3ccccc3)c2n1

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with (bromomethyl)benzene via General Procedure C to give 4-(9-benzyl-2-chloro-9H-purin-6-yl)morpholine which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 92.2 mg of 143 as a white solid. MS (Q1) 388.2 (M)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Product: COC(=O)c1ccc(C#CC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1O
Yield: 81.9 %

Procedure:
Following the basic procedure of Example 1(b), by reacting 4.2 g (0.02 mol) of 3-tert-butyl-4-methoxybenzoyl chloride with 5 g (0.02 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 6 g (81%) of the expected compound were obtained, after purification by chromatography on a silica column eluted with dichloromethane, in the form of a brown oil.
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][C:5](=[O:29])[CH2:6][C:7]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20].COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:24]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:20])([F:22])[F:21])[O:23][C:3](=[O:30])[CH2:4][C:5](=[O:29])[CH2:6]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccccc1OC(F)(F)F)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: O=C1CC(=O)OC(CCC#Cc2ccccc2OC(F)(F)F)(C2CCCC2)C1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-(2-trifluoromethoxy-phenyl)-non-8-ynoic acid methyl ester (72 mg, 0.17 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 25 mg, 37%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](Br)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[N+:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>CO.C1(P([Pd-4](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)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2c1OCC2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)cc2c1OCC2

Procedure:
m.p. 53-57 ° C.; from 5-bromo-2,3-dihydro-7-benzofurancarboxylic acid methyl ester (1.0 g), tetrakis(triphenylphosphino)palladium(0) (103 mg), 2 M sodium carbonate (7.0 mL) and 3-nitrophenylboronic acid (741 mg) in methanol (5 mL).
Reaction SMILES: [N:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[OH:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>CN(C=O)C>[OH:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]([NH:1][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([CH3:11])[CH3:12])=[O:3]
Reactant: CCOC(=O)C(N=C=O)C(C)C
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1O)C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
To a solution of ethyl 2-isocyanato-3-methybutyrate (333 mg, 1.95 mmol) in DMF (1.0 ml), 2-hydroxy-4-nitroaniline (300 mg, 1.95 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel gave desired product (420 mg, 66%). EI-MS m/z 326 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([O:20][C:21]([CH3:23])=[CH2:22])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(OCC)(=O)C.[F-].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH2:22][C:21](=[O:20])[CH3:23])[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C(C)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of (3-bromobenzyloxy)(tert-butyl)dimethylsilane (16.72 g), isopropenyl acetate (9.2 mL), tri-n-butyltin methoxide (24 mL), palladium(II)acetate (0.625 g) and tri(o-tolyl)phosphine (1.70 g) in anhydrous toluene (65 mL) was heated at reflux at 100° C. for 5 hours and then left to cool overnight. The mixture was diluted with ethyl acetate (130 mL) and 4 molar aqueous potassium fluoride (80 mL) and stirred vigorously for 20 minutes. Diatomaceous earth was added and the suspension was then filtered through diatomaceous earth, washing the residue well with ethyl acetate. The combined filtrate and washings were dried over anhydrous magnesium sulphate and concentrated in vacuo and purified by flash chromatography on silica eluting with isohexane, 10% dichloromethane in isohexane and 20% diethyl ether in isohexane to afford the subtitled compound as a yellow oil. Yield 13.71 g.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10]C)=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([OH:10])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)cc1F
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a cooled (−78° C.) solution of 6-fluoroveratraldehyde (2 g, 10.9 mmol) in dichloromethane (40 mL) was added a solution of boron tribromide in dichloromethane (1M, 44 mL, 44 mmol, 4.0 eq.). The reaction was allowed to reach room temperature and was stirred overnight. The reaction mixture was partitioned between ice water and diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water dried over sodium sulfate and filtered. Volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (1.71 mg, quant.) as a dark solid
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.N1C[C@H]([OH:55])[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][C@@H:26]([OH:55])[C@@H:24]([OH:25])[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]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2C[C@@H](O)[C@@H](O)C2)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 (3R,4S)-pyrrolidine-3,4-diol and isolated as light-yellow gum (10.3 mg, 54%). MS(m/e): 403.4 (MH+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:4]([C:2]([O:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COC(=O)Oc1ccccc1
Yield: 92.8 %

Procedure:
13.5 ml (105.6 mmol) of phenyl chloroformate are added, dropwise, at ambient temperature to a solution of 10 g (96.15 mmol) of ethyl glycolate and 27 ml (192.3 mmol) of triethylamine in 20 ml of toluene and the mixture is stirred at ambient temperature for 2 h. The salt formed is separated and the filtrate is concentrated under reduced pressure to obtain 20 g of oily product, which are used without modification in the following step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]1([CH2:26][OH:27])[CH2:25][NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:25][C:22]([F:21])([CH2:26][OH:27])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OCC1(F)CNC1
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(CO)C1
Yield: 42.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (3-fluoroazetidin-3-yl)methanol (CAN 1268520-93-9, 8.87 mg, 84.4 μmol) to obtain the title compound (11 mg, 42%) as colorless liquid, MS (ESI): m/e=372.2 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 620 mg (1.06 mmol) (R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 7 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 275 mg (2.13 mmol) N,N-diisopropylethylamine and 158 mg (1.38 mmol) methanesulfonyl chloride at room temperature. After stirring for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 618 mg (88%) of the title compound as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](=[O:23])(=[O:22])[NH:19][CH2:20][CH3:21])=[C:13]3[N:12]=[CH:11][C:10]=2[C:24](OCC)=[O:25])=[C:4]([CH3:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH2:20]([NH:19][S:18]([C:17]1[CH:16]=[N:15][N:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:29])=[C:10]([C:24]([N:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39]3)=[O:25])[CH:11]=[N:12][C:13]=12)(=[O:22])=[O:23])[CH3:21]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCNS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3C)c(C(=O)OCC)cnc12
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 6.6 %

Procedure:
Using ethyl 7-(4-chloro-2-methylphenylamino)-3-(N-ethylsulfamoyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.33 g, 0.77 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.26 g, 1.44 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.029 g, 6%) was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCC(O)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:10][OH:11].[C:12]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:14][CH3:15])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:8][CH2:9]2)=[N:4][C:3]=1[CH2:10][O:11][C:19]1[CH:20]=[CH:21][C:16]([C:12]([O:14][CH3:15])=[O:13])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1nc(C2CC2)oc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2nc(C3CC3)oc2Br)cc1
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)methanol (intermediate D3.1, 0.10 g, 0.46 mmol) in THF (4 ml) was added 4-carbomethoxyphenol (0.11 g, 0.69 mmol), Ph3P (0.18 g, 0.69 mmol) and DIAD (0.13 ml, 0.69 mmol). After 2 h at rt, the reaction was concentrated and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to give methyl 4-[(5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)methoxy]benzoate. LCMS [M+H]+=352.2.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[CH3:25][C:26]1[N:27]=[CH:28][S:29][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:32]([CH2:31][C:30]3[S:29][CH:28]=[N:27][C:26]=3[CH3:25])[CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: Cc1ncsc1CNCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3scnc3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde(0.423 g) and acetic acid(0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine(0.36 g). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride(0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound(0.37 g) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CCN
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)CCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirring, refluxing suspension of 84.4 g (0.4) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 750 ml ethanol was added gradually a solution of 2-diethylaminoethylamine in 50 ml ethanol. The solution was refluxed and stirred for 1 hr; the solvents were then removed in vacuo. The residue was taken up in 300 ml chloroform; the solution was washed with three 150-ml portions of water, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 123 g (100%) of the product.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([C:17]#[C:18][C:19]3[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)=[C:15]([CH3:26])[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>O.C1COCC1>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([C:18]#[C:17][C:16]2[C:11]([N:8]3[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:27])=[O:2])[CH2:6][CH2:7]3)=[N:12][CH:13]=[N:14][C:15]=2[CH3:26])=[CH:24][CH:23]=1
Reactant: COC(=O)CC1CCN(c2ncnc(C)c2C#Cc2ccc(N)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc(N2CCC(CC(=O)O)CC2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.87 g (7.85 mmol) {1-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-yl}-acetic acid methyl ester using 0.82 g (19.6 mmoL) LiOH in 10 mL water and 40 mL THF. The reaction mixture is stirred over night at 50° C. The THF is removed under reduced pressure and the residue is taken up DCM and MeOH and separated from insoluble material. The filtrate is dried over MgSO4 and the solvent is removed under reduced pressure. After drying 2.9 g (95%) of crude product is obtained which is used for the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CN(C=O)C.CCOCC.Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:5]([CH3:23])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]3[CH2:20][N:19]([CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[C:18](=[O:21])[N:17]3[CH3:22])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:32])=[CH:26][CH:27]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 99 mg of 2-bromomethyl naphthalene is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 51 mg (51%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.82-7.79 (m, 3H), 7.67 (s, 1H), 7.50-7.44 (m, 2H), 7.35 (d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=8.6 Hz), 6.93 (t, 2H, J=8.4 Hz), 6.87-6.83 (m, 2H), 6.71 (d, 2H, J=8.6 Hz), 5.11 (bs, 1H), 4.53 (s, 2H), 3.95-3.90 (m, 2H), 3.85-3.70 (m, 1H), 3.46 (t, 1H, L=8.7 Hz), 3.23, 3.09 (ABq, 2H, J=14.0 Hz), 3.07 (t, 1H, J=8.7 Hz), 2.89 (s, 3H), 2.26-2.18 (m, 1H), 1.96-1.87 (m, 1H), 1.36 (s, 3H). HRMS (ES+) m/z exact mass calcd for C33H34N2O5F (m+1) 557.2452, found 557.2439.