Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]CC)(=[O:10])[C:5]([O:7][CH2:8][CH3:9])=O.[OH:14][C:15]1[C:23](C(=O)C)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][CH2:19]2>CC1C=CC=CC=1>[O:14]=[C:15]1[C:16]2[CH:17]=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:9]=3[C:8]=2[O:7][C:5]([C:4]([OH:11])=[O:10])=[CH:23]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc2c(c1O)CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(=O)c2ccc3c(c2o1)CCC3
Yield: 57 %

Procedure:
Sodium methylate (24 g) was stirred in methylbenzene (300 ml). A mixture of diethyl oxalate (0.16 mol) and intermediate (2-a) (0.16 mol) in methylbenzene (10 ml) was added dropwise. This mixture was stirred and refluxed for 2 hours. The resulting precipitate was filtered off and dried. The solid was stirred in a mixture of hydrochloric acid (10 ml) and acetic acid (500 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured out into water. The resulting precipitate was filtered off and dried (vacuum), yielding 21 g of 4,7,8,9-tetrahydro-4-oxocyclopenta[h]-1-benzopyran-2-carboxylic acid (interm. 3-a).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[CH3:20][S:21]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2nnn(OS(C)(=O)=O)c2c1
Yield: 76.6 %

Procedure:
In chloroform (80 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5.1 g) under stirring, and thereto is added dropwise a solution of methanesulfonyl chloride (5.73 g) in chloroform (20 ml) at a temperature of less than 10° C. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 40 ml. After dissolving the precipitated crystals by heating, the mixture is allowed to stand. The precipitated crystals are separated by filtration to give 1-methanesulfonyloxy-6-vinyl-1,2,3-benzotriazole (9.1 g), melting point: 129°-129.5° C. The filtrate is concentrated, and the resulting residue is recrystallized from benzene to give additionally the desired product (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].O=[C:26]([CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]3[CH2:33][O:34][CH2:35][CH2:36][C:37]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOC(=O)C(=O)C1COCCC1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc2c1COCC2
Temperature: 50 °C

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (418 mg, 1.36 mmol) and potassium carbonate (469 mg, 3.40 mmol) in EtOH (8mL) were stirred for 10min at 50° C. Ethyl 2-oxo-2-(4-oxotetrahydro-2H-pyran-3-yl)acetate (272 mg, 1.36 mmol) was added slowly and the reaction was stirred at 50° C. over night. The crude product was partitioned between DCM and water. The organic phase was dried and solvent evaporated and used as such in the next step. MS (ES+) m/z 410.0 (M+H)+
Reaction SMILES: [OH:1][C@H:2]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C@H:3]([NH:5]C(=O)OCC1C=CC=CC=1)[CH3:4]>C(O)C.[C].[Pd]>[NH2:5][C@H:3]([CH3:4])[C@H:2]([OH:1])[CH2:16][O:17][Si:18]([CH:19]([CH3:21])[CH3:20])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[Si](OC[C@@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[Si](OC[C@@H](O)[C@@H](C)N)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
Benzyl {(2R,3S)-3-hydroxy-4-[(tripropan-2-ylsilyl)oxy]butan-2-yl}carbamate (3.70 g, 9.35 mmol) synthesized in Example (89d) was dissolved in ethanol (30 mL), and palladium carbon (1.00 g) was added, followed by stirring at room temperature for 8 hours under hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure to afford the desired compound (2.65 g, yield ˜100%) as a pale yellow liquid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.068 g, 83%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.120 g, 0.26 mmol) and methylamine (1.24 g, 40.0 mmol). mp 147-149° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25]O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2
Reactant: OCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 6B, 700 mg, 1.698 mmol) in anhydrous dichloromethane (25 mL) was added phosphorous tribromide (0.240 mL, 2.55 mmol) slowly at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature overnight. Next, 10 mL of ice water was added at 0° C. to quench the reaction. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (20 mL) and filtered over CELITE®. The aqueous layer was separated, combined with the aqueous layer from before and extracted with dichloromethane (2×20 mL). The combined organic solutions were dried over sodium sulfate, filtered through a silica gel pad that was rinsed with dichloromethane, and concentrated under reduced pressure to give 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (580 mg, 1.220 mmol, 71.9% yield) as a yellow solid. LC/MS M+1=477.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[Na+].[CH2:27](Br)[CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4.94 g (15 mmol) of N-benzyloxycarbonyl-tyrosine-methyl ester is dissolved in 25 ml of anhydrous N,N-dimethylformamide and mixed at 5° C. under argon with 0.61 g (15.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 10 minutes, then 1.91 g (15.5 mmol) of propyl bromide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another two hours. For working-up, the batch is taken up in ethyl acetate and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOc1ccc2ccccc2c1

Procedure:
450 g of β-naphthol, 200 ml of ethanol and 50 ml of 98% sulfuric acid were mixed and after finishing the generation of heat the mixture was heated on a steam bath for 4 hours. After allowing to stand and cool, the lower layer was removed. Then the procedures wherein to the residue were added 40 ml of ethanol and 20 ml of 98% sulfuric acid, the mixture was heated on a steam bath for 3 hours and the lower layer was removed after allowing to stand and cool were repeated three times. The organic layer was washed with water to which was added an aqueous solution of sodium hydroxide (40 g of sodium hydroxide dissolved in 1 liter of water) and the mixture was warmed and shaked. While it was warm, the lower layer was removed, the upper layer was poured into an aqueous solution of sodium hydroxide and cooled to solidified. The solid was collected by filtration, washed with water and air-dried. Yield: 461 g.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[Na].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C=C(CBr)C(=O)O
Reactant: CCCCOc1ccc(S(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(CS(=O)(=O)c1ccc(OCCCC)cc1)C(=O)O

Procedure:
A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), 4-butoxybenzenesulfinic acid, sodium salt (3.1 g, 13 mmol), sodium carbonate (1.9 g, 18 mmol) and dimethylformamide (20 mL) is refluxed overnight. The reaction mixture is then partitioned between ethyl acetate and aqueous 10% hydrochloric acid and the organic phase is concentrated in vacuo. The concentrate is chromatographed over silica gel 60 (230-400 mesh) with chloroform/methyl alcohol/acetic acid (94/5/1) and the eluate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[N:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCCC1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CC2CCCCC2=NO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(3-benzyloxy-4-nitrobenzyl)-cyclohexanone (1.0 g, 2.95 mmol), hydroxylamine hydrochloride (407 mg, 5.9 mmol) and sodium acetate (726 mg, 8.85 mmol) in MeOH (20 mL)/water (4 mL) is stirred at RT for 18 h. The resulting precipitate is filtered and washed with water to give the title compound as a yellow solid: (M+1)+=355.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH:31][C:32]([CH3:39])([CH3:38])[C:33]#[C:34][C:35](O)=[O:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:35](=[O:36])[C:34]#[C:33][C:32]([OH:31])([CH3:39])[CH3:38])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CC(C)(O)C#CC(=O)O
Product: CC(C)(O)C#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 25.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-hydroxy-4-methylpent-2-ynoic acid, to afford the title compound (8.0 mg, 25.1%). Data: UPLC (C) Rt: 1.53 min; m/z 510.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.CS(C)=[O:16].[O-]Cl=O.[Na+]>O.CC(C)=O>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([C:12]([OH:16])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2c(C=O)csc12
Reactant: CS(C)=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CSc1ncnc2c(C(=O)O)csc12
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (513 mg, 3.29 mmol) was dissolved in water (2 mL) and then 4-(methylthio)thieno[3,2-d]pyrimidine-7-carbaldehyde (300 mg, 1.68 mmol) dissolved in acetone (3 mL) and DMSO (3 mL) was added thereto at 0° C. NaClO2 (194 mg, 2.15 mmol) dissolved in water (2 mL) was added at the same temperature to the reaction mixture, which was stirred for 2 hours. After the reaction was completed water (10 mL) was further added to the reaction mixture, which was stirred for 2 hours and filtered to obtain a solid. The solid was washed with water several times and dried with N2 gas to obtain the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8]([N:48]2[CH2:47][CH2:46][N:45]([CH:42]3[CH2:43][CH2:44][O:39][CH2:40][CH2:41]3)[CH2:50][CH2:49]2)=[O:9])=[CH:4][C:3]=1[Cl:38]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 8i from 80.0 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-4-oxo-butanoic acid and 24.5 mg (0.14 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:20])[CH3:12])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 189.9 %

Procedure:
A mixture consisting of 44.76 g (0.3 mole) of the 4-dimethylaminobenzaldehyde thus obtained, 76.3 g (0.63 mole) of dimethylaniline and 247 g of a 20% aqueous HCl solution was condensed by stirring it at 100° C. for 8 hours to obtain 106.4 g of tris(4-dimethylaminophenyl)methane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]#[N:23])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:24]S(O)(=O)=O>>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]([NH2:23])=[O:24])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reactant: O=S(=O)(O)O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To concentrated H2SO4 (90 mL) cooled with an ice bath was added 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g, 130 mmol) in portions such that the internal temp did not exceed 50° C. but did not go below 25° C. After complete addition, the mixture was stirred in the ice bath until the reaction started to cool, at which point the reaction was removed from the ice bath and the mixture was heated to 50° C. The reaction was cooled to ambient temperature and the mixture added to ice water slowly over 3 minutes (about 1400 mL of 30% ice in water). The mixture was further cooled in an ice bath to 5° C. The mixtures was neutralized to about pH 10 with 4M NaOH (about 800 mL) while maintaining the internal temperature below 20° C., at which point a solid formed. The mixture was stirred for 20 minutes. The mixture was filtered and washed with MTBE (5×150 mL), hexanes (5×100 mL), and dried at under vacuum to afford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43 g, 96%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]4([CH3:32])[CH2:31][O:30][CH2:29]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CO.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>[F:35][C:36]1[C:41]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]5([CH3:32])[CH2:29][O:30][CH2:31]5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
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: [K+]
Solvent: CO
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1

Procedure:
A vial was charged with (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (50.0 mg, 0.101 mmol), 2-fluoropyridin-3-ylboronic acid (21.33 mg, 0.151 mmol), potassium carbonate (69.7 mg, 0.505 mmol), and Pd(PPh3)4 (11.66 mg, 10.09 μmol). The vial was flushed with Ar (g), then dioxane (505 μL) and water (0.25 mL) were added in sequence. The vial was sealed and placed in a 70° C. oil for 1 hour. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give a pink solid. The solid was dissolved in MeOH and loaded onto a 500-mg SCX-2 column. The column was first eluted with methanol, then with 2N ammonia in methanol to remove the product. The filtrate was evaporated to give (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as pale yellow solid. Found MS: MH+=443.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][CH:29]([F:33])[C:30](Cl)=[O:31]>>[F:28][CH:29]([F:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C(F)F
Product: C[C@H](NC(=O)C(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and difluoroacetyl chloride (23 mg, 150 μmol). Yield 21 mg (95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:13])=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH:29]1([NH:32][C:10](=[O:12])/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH3:13])[CH2:31][CH2:30]1
Reactant: C/C(=C\C(=O)O)c1cccc(F)c1
Reactant: NC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C/C(=C\C(=O)NC1CC1)c1cccc(F)c1

Procedure:
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutes. To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:21][CH2:22][CH3:23])(=[O:20])[CH:12]=CC1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6](/[CH:7]=[CH:12]/[C:11]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: Cc1ccc(F)cc1C=O
Product: CCOC(=O)/C=C/c1cc(F)ccc1C

Procedure:
5-Fluoro-2-methylbenzaldehyde (40.58 g; 294 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 40.81 g. of the title compound.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:37])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=3)=[N:24][N:23]=2)[C@H:9]([OH:8])[CH3:37])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O)o2)cc1
Temperature: 10 °C
Yield: 78.3 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide (246 mg, 0.45 mmol) in THF (20 mL) was added TBAF (0.55 mL, 0.55 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture was allowed to warm to 10° C. over 2.5 h and quenched with sat. aq. NH4Cl (30 mL). The resulting mixture was partitioned between H2O (25 mL) and EtOAc (35 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (60-100% EtOAc in hexanes) to provided the title compound as a colourless solid (150 mg, 78%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.47 (s 1H), 7.90 (dm, J=8.8 Hz, 2H), 7.81 (dm, J=8.8 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 5.86 (d, J=8.8 Hz, 1H), 5.04 (dd, J=5.3, 8.6 Hz, 1H), 4.68 (br s, 1H), 4.51 (pentet, J=6.1 Hz, 1H), 2.36 (s, 3H), 2.12 (s, 3H), 1.42 (d, J=6.5 Hz, 3H).