Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using [5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.CCOC(C)=O.[CH3:21][CH2:22][CH2:23]CCC>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:23][CH:22]=[CH2:21]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)ccc1O
Reaction time: 1.5 h

Procedure:
The neat allyl ether 22-2 from Step A (7.0 g, 38.6 mmol) was heated in an oil bath at 230 ° C. for 1 h. The reaction was followed by NMR and was found to be complete after 90 min. The resulting brown oil was cooled and subjected to column chromatography (1:1 EtOAc/Hexane) to afford 22-3 as a white solid.
Reaction SMILES: [CH2:1]([C:8]([NH2:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C1O[N:17]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(Cl)Cl>[CH2:1]([C:8]([NH:13][NH:17][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:11][CH3:12])[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Reactant: CCC(N)(CC)Cc1ccccc1
Solvent: ClCCl
Product: CCC(CC)(Cc1ccccc1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.68 g of 3-benzylpentan-3-amine was dissolved in 20 mL of methylene chloride, mixed with 4.8 g (18 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice, and stirred at room temperature for 30 minutes, and the reaction solution was washed with 10% aqueous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 20:80) to give 1.62 g of the desired product as a light brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>CC(C)=O>[O:29]1[CH2:28][CH:27]1[CH2:25][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:17][CH:16]=1
Reactant: Oc1ccc(C=Cc2cccc3[nH]ccc23)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=Cc1cccc2[nH]ccc12)c1ccc(OCC2CO2)cc1
Reaction time: 5 h

Procedure:
A mixture of 5.8 g of the product of Step A, 120 ml of acetone, 3.6 g of potassium carbonate and 9.6 ml of epichlorhydrin was refluxed for 24 hours with stirring under an inert atmosphere. Then, 9.6 ml of epichlorhydrin were added and reflux was continued for 5 hours. After filtering, the solvent was evaporated under reduced pressure at 60° C., and the fractions with Rf=0.35 were recovered by chromatography on silica (eluent:methylene chloride) to obtain 5.25 g of 4-[2-[4-[(2-oxiranyl)-methoxy]-phenyl]-ethenyl]-1H-indole melting at ≃128° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[NH:6][C:7]1[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[NH:10][C:11](=O)[C:12]=1[N+:13]([O-:15])=[O:14])#[N:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:35])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:35][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[N:10]=1
Reactant: CC(=O)Nc1nc(Nc2cccc(C#N)c2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Nc2cccc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N1-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide (2.5 g) was suspended in 50 ml of acetonitrile, then 2.64 g of tetraethylammonium chloride, 1 ml of N,N-dimethylaniline and 4.5 ml of phosphorus oxychloride were added and the mixture was heated under reflux for 5 hours. The reaction solution was returned to room temperature and added to ice-water and the mixture was stirred for 30 minutes. The resulting crystals were collected by filtration, washed with water and dried to give 2.5 g of N1-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide. The yield was 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:33][CH2:32][CH2:31][CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2cc3c(Nc4ccc(F)c(Cl)c4)c(C#N)cnc3cn2)CC1
Yield: 71 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-(4-methylpiperazin-1-yl)propan-1-amine. The crude product was purified by flash column chromatography (10% methanol in methylene chloride) to give a yellow solid (0.102 g, 71%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 2.2 (s, 3 H) 2.4 (m, 8 H) 3.3 (m, 4 H) 6.9 (m, 2 H) 7.4 (s, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (d, J=7.1 Hz, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.7 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.O.NN>C(O)C>[Br:1][C:2]1[CH:15]=[CH:6][C:5]2[N:16]3[C:17]([CH2:33][NH2:34])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:23]([C:24]3[CH:25]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, 5-bromo-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-bromo-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)cc(C)cc21
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2c1cc(C)c([N+](=O)[O-])c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride (35 ml), and nitric acid (d=1.5, 0.92 ml) dissolved in acetic anhydride (15 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for one hour and poured into ice water. Saturated aqueous sodium hydrogencarbonate was added to neutralize the mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent : chloroform-methanol=1:0-100:1) to give 2.4 g of the title compound (2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[CH3:36]>C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:43][CH:42]=1)[CH3:36]
Reactant: OC/C=C(\c1ccccc1)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 52.7 %

Procedure:
Reaction of (E)-3-(4-furan-2-yl-phenyl)-3-phenyl-prop-2-en-1-ol (475 mg, 1.72 mmol), tributylphosphine (0.63 ml, 2.58 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (451 mg, 1.89 mmol) and azodicarboxylic dipiperidide (650 mg, 2.58 mmol) in benzene in an identical manner to example 3 gave the title compound (450 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@@H:15]([C:18]3([CH3:21])[CH2:20][CH2:19]3)[CH2:14][C@H:13]1[CH2:12][O:11][NH:10]2.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:10][C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:17][O:16][C@@H:15]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[CH2:14][C@H:13]1[CH2:12][OH:11]
Reactant: CC1([C@H]2C[C@H]3CON[C@@]3(c3ccc(F)cc3F)CO2)CC1
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: CC1([C@H]2C[C@@H](CO)[C@](N)(c3ccc(F)cc3F)CO2)CC1
Yield: 148 %

Procedure:
rel-(3aR,5R,7aS)-7a-(2,4-Difluorophenyl)-5-(1-methylcyclopropyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C57) (1.48 g, 5.00 mmol) was converted to the product according to the method described for the synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. The product was obtained as a dark oil (2.2 g), which was taken directly to the following step without additional purification.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=O)=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.CN(C1C=CC(C2CC(=O)C3C(=CC=CC=3)O2)=CC=1)C>O.[Zn]>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:20]2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CN(C)c1ccc(C=CC(=O)c2ccccc2O)cc1
Agent: CN(C)c1ccc(C2CC(=O)c3ccccc3O2)cc1
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CN(C)c1ccc(C2CCc3ccccc3O2)cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
4-(N,N-dimethylamino)-2'-hydroxychalcone (6.6 g.) was boiled under reflux with 2-N hydrochloric acid (100 ml.) for 3 hrs. The resulting solution of 4'-(N,N-dimethylamino) flavanone hydrochloride was added to a suspension of amalgamated zinc (from zinc powder (40 g.) and mercuric chloride (0.8 g.)) in water 30 ml. and the mixture stirred at 45° C. for 45 min. The residual zinc was separated by decantation from the aqueous liquor, stirred with acetic acid (150 ml.) and filtered. The zinc was further washed with acetic acid and the combined washing and filtrate were diluted with water and extracted with toluene. The extract was washed with water, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on neutral alumina and the first fraction evaporated to give crystalline 4'-(N,N-dimethylamino) flavan which was recrystallised from methanol, and then 60°-80° C. petroleum ether, 0.7 g., m.p. 77°-78° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.[Cl-].[NH4+]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:12][NH2:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
15 g of sodium hydride at 60% in oil are suspended in 200 ml of anhydrous THF. A solution of 69.5 g of 3,4-dichlorophenylacetonitrile in 500 ml of THF is added dropwise over 30 minutes and then the reaction mixture is stirred at RT for 1 hour. The mixture is cooled to -20° C. and a solution of 85 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 100 ml of THF is added. The mixture is allowed to return to RT and after 2 hours it is poured over a solution of 50 g of ammonium chloride in 3 liters of water. The mixture is extracted with ether, washed with a saturated solution of sodium chloride, decanted, dried over MgSO4 and concentrated. The residue is chromatographed on silica gel, eluting with a mixture of toluene and an AcOEt gradient (3 to 5%). The pure product fractions are concentrated to give 77 g of expected product in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:49]=[CH:48][C:27]([C:28]([N:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3/[C:34](=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])/[C:33]([F:47])([F:46])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:47][C:33]1([F:46])[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:49][CH:48]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2/[C:34]/1=[CH:41]/[C:42]([O:44][CH3:45])=[O:43]
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3cccc(C)c3)cc2)CCC1(F)F
Yield: 90.9 %

Procedure:
Using 277 mg of 2-(3-methylphenyl)benzoic acid, 0.127 ml of oxalyl chloride and 180 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 249 mg of methyl (Z)-[4,4-difluoro-1-[4-[2-(3methylphenyl)benzoylamino]benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19]OS(C)(=O)=O)([CH3:18])[CH2:13]1.[C:25]([OH:28])(=[S:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][S:27][C:25](=[O:28])[CH3:26])([CH3:18])[CH2:13]1
Reactant: CC(O)=S
Reactant: C[C@]1(COS(C)(=O)=O)CCCN(C[C@H]2COc3ccccc3O2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@]1(C)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 95 °C
Yield: 90.7 %

Procedure:
A mixture of methanesulfonic acid (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl ester (927 mg, 2.61 mmol), thioacetic acid (373 μl, 399 mg, 5.24 mmol) and K2CO3 (721 mg, 5.22 mmol) in DMF (35 ml) was heated at 95° C. for 10 h. The mixture was evaporated to dryness, dissolved in DCM and washed two times with sat. aq NaHCO3. The organic phase was washed with brine, dried (Na2SO4) and evaporated to dryness to give 794 mg of the title compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[O:12][C:7]=2[CH:6]=1)[C:2]#[CH:3].[C:19]([N:22]=[C:23]=[S:24])(=[O:21])[CH3:20]>C1COCC1>[CH2:3]=[C:2]1[S:24][C:23](=[N:22][C:19](=[O:21])[CH3:20])[N:4]([C:5]2[CH:18]=[CH:17][C:8]3[O:9][C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[O:12][C:7]=3[CH:6]=2)[CH2:1]1
Reactant: CC(=O)N=C=S
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=NC(C)=O)S1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
An alternative procedure to prepare the titled compound follows. The propargylaniline (Example 22A, 31.08 g, ˜119 mmol) was dissolved into THF (300 mL) and treated with acetylisothiocyanate (11.5 mL, 131 mmol). After being stirred at room temperature briefly, it was heated to approximately 55° C. overnight, and at 60-65° C. for another 6 days. Then the mixture was concentrated and reconcentrated from CH2Cl2/hexanes to give a semi-solid which was mixed into 3:1 Et2O/hexanes and chromatographed on neutral alumina (40% Et2O/hexanes then 40% Et2O/CH2Cl2) to give the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:37][CH2:35][CH2:34][CH2:33][OH:39])[N:18]=[C:17]([C:31]3[N:36]=[C:35]([O:37][CH2:38][CH2:22][CH2:23][OH:28])[CH:34]=[C:33]([O:39][CH2:40][CH2:19][CH2:20][OH:21])[N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)nc(-c2nc(Cl)c(Oc3ccccc3OC)c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)n2)n1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2nc(OCCCO)cc(OCCCO)n2)nc1OCCCO
Yield: 100.4 %

Procedure:
A solution of 4-t-butyl-N-[6-chloro-2-(4,6-dimethoxy-2-pyrimidinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-benzenesulfonamide (409 mg) in anhydrous dimethylformamide (2.4 ml) was added dropwise to the above mixture while being cooled on ice. The resultant mixture was stirred for 3.5 hours at 60° C. The reaction mixture was poured into cold 1N HCl, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give obtain 4-t-butyl-N-[2-(4,6-di(3-hydroxypropyloxy)-2-pyrimidinyl)-6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-benzenesulfonamide (250 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27](O)=[O:28].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]1=2)=[O:28]
Reactant: O=C(O)Cc1nc2ccccc2o1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1nc2ccccc2o1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), benzooxazol-2-yl-acetic acid (0.023 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.022 g, 53%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.71 (m, 1H), 7.53 (m, 1H), 7.45 (dd, J=8.8, 4.8 Hz, 2H), 7.34 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 4.25 (s, 2H), 3.88 (m, 2H), 2.83 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H17FN4O2 [M+H]+ 377.1, found 377.1.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11]C)=O)[CH3:3].[C-]#[N:14].[Na+]>N.CO>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([NH2:14])=[O:11])[CH3:3]
Reactant: [C-]#N
Reactant: CCN1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CO
Product: CCN1CCC[C@H]1C(N)=O
Yield: 632.9 %

Procedure:
Crude methyl (S)- 1-ethyl-2-pyrrolidinecarboxylate hydrochloride (2.1 g, 0.01 mol; Example 6A) and NaCN (50 mg, 0.001 mol) in 30 ml 9M NH3 in MeOH was heated to 45° C. in a sealed glass flask for 2 days. GLC showed a conversion of 95% and usual work-up afforded 0.9 g (63%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH2:4]Cl.C(O)(=[O:16])C.C1N2CN3CN(C2)CN1C3.Cl>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc(CCl)c(C)c([N+](=O)[O-])c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cc(C=O)c(C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture constituted by 2,5-dimethyl-3-nitrobenzyl-chloride (A) prepared according to M. J. WINCHESTER and F. D. POPP, J. Het. Chem. 12, p. 547 (1975) (610 g), acetic acid (1280 ml, water (1280 ml) and hexamethylene tetramine (855 g) was heated with reflux under stirring for 2 hours. 1037 ml of concentrated hydrochloric acid were then added in 10 minutes and the mixture was again heated with reflux for 20 minutes. This mixture, cooled to 0° C., gave a solid which was filtered off, dried and recrystallised from cyclohexane (4 liters) to give 290.5 g (53%) of yellow needles corresponding to the aldehyde of formula B, melting point : =90°-93° C.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[B:28]1[O:32]C(C)(C)[C:30](C)(C)[O:29]1)[O:6][C:7]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:10]([C:11]#[N:12])=[CH:9][N:8]=1)=O.[BH4-].[Na+].OS([O-])(=O)=O.[Na+]>CO>[OH:32][B:28]1[C:27]2[CH:26]=[CH:25][C:5]([O:6][C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][C:3]=2[CH2:30][O:29]1
Reactant: CC1(C)OB(c2ccc(Oc3cc(OCCOC4CCCCO4)c(C#N)cn3)cc2C=O)OC1(C)C
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc(Oc2ccc3c(c2)COB3O)cc1OCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (0.5 g, 1.02 mmol) in methanol (3 mL) at 0° C. was added sodium borohydride (0.07 g, 2.04 mmol). After 1 h at room temperature, the solution was cooled in an ice bath and 1M NaHSO4 (2.6 mL, 2.6 mmol) was added until pH reached to 4˜5. The resulting mixture was sonicated and stirred at 0° C. for 1 h. The white solid that separated was filtered, washed with MeOH and lyophilized to yield the title compound D118 (0.1 g, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 8.46 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15-7.09 (m, 1H), 7.02 (s, 1H), 4.99 (s, 2H), 4.71 (s, 1H), 4.49-4.40 (m, 2H), 4.02-3.91 (m, 1H), 3.84-3.73 (m, 2H), 3.49-3.41 (m, 1H), 1.72-1.58 (m, 2H), 1.55-1.41 (m, 4H); MS (ES) m/z: 397 (M+1)+; HPLC purity 97.55% (Maxplot), 97.65% (220 nm).