Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4C(=O)C5=CC=CC=C5C4=O)[N:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.C(N)CN>CCO>[NH2:24][CH2:23][C:19]1[N:18]=[C:17]([CH2:16][N:13]2[C:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CN4C(=O)c5ccccc5C4=O)n3)c2n1
Solvent: CCO
Solvent: NCCN
Product: NCc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 7-(2-furyl)-3-(6-phthalimidomethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (210 mg, 0.465 mmol) in EtOH (50 mL) was treated with ethylenediamine (62 μl, 0.929 mmol), stirred for 3 h at 90° C. and the resulting clear solution, cooled to room temperature and concentrated in vacuo to give 3-(6-aminomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine. A solution of this material in pyridine (10 mL) at 0° C. was treated with acetyl chloride (109 ml, 1.53 mmol), stirred for 10 min, poured into water (70 mL), extracted with EtOAc (3×20 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (110 mg, 65%) as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:31](I)([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:31]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with isopropyl iodide and cesium carbonate in N,N-dimethylacetamide to give N-isopropyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 534.8 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][N:16]([C:21]4[CH:22]=[C:23]([C:27]([N:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:31][CH2:30]5)=[O:28])[N:24]=[CH:25][N:26]=4)[CH2:17][CH2:18]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(N3CCc4cc(Cl)ccc4NC3=O)CC2)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg (0.36 mmol) 7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 87.6 mg (0.34 mmol) (6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 63 μL (0.37 mmol) DIPEA in 2.5 mL DMF. The reaction mixture was stirred overnight at RT, then concentrated by rotary evaporation using the rotary evaporator and purified by preparative HPLC. The corresponding product fractions were combined and evaporated down using the rotary evaporator. The residue was taken up in DMF and combined with methanol. The substance was precipitated, suction filtered, washed with a little methanol and dried.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.08 ml, 6.86 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis-(trimethylsilyl)amide (1.0 M solution in THF, 6.86 ml, 6.86 mmol) slowly. The mixture was stirred at rt for 40 min, before a solution of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone (1.03 g, 3.43 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography 5% EtOAc in hexane gradient to 25% EtOAc in hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an oil (0.98 g, 88%): 1H NMR (DMSO-d6) δ 6.99-6.79 (m, 3H, Ar), 6.65-6.62 (2ts, 1H, Ar), 6.46-6.44 (2ds, 2H, Ar), 6.25 (s, 0.47H, double bond proton of one isomer), 6.20 (s, 0.54H, double bond proton of the other isomer), 4.33-4.24 (m, 4H, 2CH2), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 179.5, 160.8, 160.7, 145.7, 144.8, 143.3, 143.0, 140.3, 139.1, 130.4, 129.7, 122.5, 121.7, 118.2, 118.1, 117.9, 117.2, 117.1, 116.6, 107.1, 106.7, 101.8, 100.9, 95.4, 94.3, 64.4, 64.2, 64.0, 64.0, 55.4, 54.9; Anal. Calcd. For C19H17NO4 (+0.05 H2O): C, 69.40; H, 5.26; N, 4.24. Found: C, 69.19; H, 5.11; N, 4.25.
Reaction SMILES: [Cl:1][C:2]1[N:7]=C(NC)[C:5]([NH2:10])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:23]2[N:24]([CH3:25])[C:26](=[O:27])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CNc1nc(Cl)ccc1N
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c2ccc(Cl)nc21
Temperature: 80 °C

Procedure:
6-chloro-N2-methylpyridine-2,3-diamine (1-2) (35 g, 222 mmol) and 1,1′-Carbonyldiimidazole (63 g, 389 mmol) were added to a round bottom flask and suspended in DMF (150 mL). The solution was heated to 80° C. in an oil bath overnight. The reaction was then suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine (×5), dried over sodium sulfate, filtered, and concentrated to produce the solid 5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3). MS (M+H)+: observed=184.2, calculated=184.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].Br[CH2:12][C:13]([CH3:15])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:14][C:13](=[CH2:12])[CH2:15][O:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1]
Reactant: Cc1cc(Br)cc(Br)c1O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1c(C)cc(Br)cc1Br
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 2,4-dibromo-6-methylphenol (2.0 g, 7.5 mmol), 3-bromo-2-methylprop-1-ene (1.5 g, 11.3 mmol), K2CO3 (3.12 g, 22.6 mmol) in DMF (15 mL) was heated at 70° C. 2 hours. The reaction was then cooled to room temperature and was diluted with water and hexanes. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 0-10% EtOAc/hexanes to give the title intermediate (1.05 g) as colorless liquid.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])=[O:4])[CH3:2].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCS(=O)(=O)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of 3-(ethylsulfonyl)-1-propanol (from step (i) above; 13.4 g, 88 mmol) and p-toluenesulfonyl chloride (16.8 g, 88 mmol) in DCM (150 mL) was treated with TEA (13.4 g, 132 mmol), added dropwise. The resulting mixture was stirred at rt for 3 h before being washed with aqueous ammonium chloride solution. The organic layer was then separated, dried and concentrated in vacuo. The product was crystallised from ether containing a small amount of DCM to yield 17.9 g (66%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)=[C:17]=[S:18]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
A solution of 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g,˜6.8 mmol) (from Step B above) in N,N-dimethylformamide (25 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (1.4 g, 7.7 mmol) (Aldrich) in N,N-dimethylformamide (30 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-(1-methylethyl)piperazine (1.8 g, quantitative yield).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1)[CH3:23]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-phenoxy-phenol as in Example 18 to afford 0.200 g (35%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H28O5 468, found 469 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
As in Example 115. (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid (1 g) and 4-nitrophenol (0.54 g) in 7 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (0.67 g). The mixture was stirred at room temperature for 2 hours. After the usual work up. the crude ester was crystallized from 2-propanol to give 0.825 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 133.5°-135° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: COc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: COc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (140 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (163 mg, 0.57 mmol, Amine-9, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)=[O:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:16][O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)N1CCC(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylaminomethylpiperidine (3.62 g, 16.9 mmol) in dichloromethane (100 mL) was added 4-formylpiperidine-1-carboxylic acid methyl ester (2.89 g, 16.9 mmol) and acetic acid (0.96 mL). The mixture was stirred at room temperature for 10 min prior to the addition of sodium triacetoxyborohydride (5.4 g, 25.5 mmol). The final mixture was stirred at room temperature for 1 h. The reaction was terminated by adding saturated sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (100 mL), and the organic layer was dried over MgSO4. Evaporation of the organic solution afforded a pale yellow oily residue. It was purified by flash silica column chromatography (CH2Cl2 to 5% MeOH/CH2Cl2), yielding the title intermediate (4.4 g). (m/z): [M+H]+ calcd for C19H35N3O4 370.27. found 370.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=[C:12]([Cl:14])[N:13]=1>CO>[Cl:14][C:12]1[N:13]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2ccsc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Scheme 6 shows the synthesis of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 starting by cyclization of methyl 2-amino-thiophenecarboxylate 15 (95 g) with chlorosulfonyl isocyanate at low temperature remains (−60° C. to −55° C.) to give thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16. Phosphorous oxychloride was added slowly to a cold solution of thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16 and N,N-dimethylaniline (0.75 equiv.) in acetonitrile while maintaining the temperature below 25° C. The mixture was then heated to 80-85° C. and stirred for 24 hours to afford dichlorothieno[2,3-d]pyrimidine 17. Morpholine (2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 in methanol and stirred at ambient temperature for 1 h to give 18.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:12][CH2:11][CH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(CO)c1cccc2c1OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(COS(C)(=O)=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 6.65 g (28.1 mmol) of 2-(2, 3-methylenedioxyphenyl)heptanol in 80 ml of methylene chloride was added 4.30 ml (30.9 mmol) of triethylamine, and 2.28 ml (29.5 mmol) of methanesulfonyl chloride was dropwise added. The reaction mixture was stirred at room temperature for 30 minutes, washed with water twice, dried over anhydrous magnesium sulfate and the solvent was evaporated to give 8.76 g of 2-(2, 3-methylenedioxyphenyl)heptyl methanesulfonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[K].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[N:9]=[C:8]([S:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(S)cc1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Sc2nc(Cl)c(C#N)cc2F)cc1

Procedure:
2,6-Dichloro-5-fluoronicotinonitrile (32.5 g) in ethanol (400 ml) was treated at room temperature with potassium salt of p-thiocresol, prepared from p-thiocresol (23.2 g) and potassium hydroxide (12.2 g), to give 2-chloro-6-(p-tolylthio)-5-fluoronicotinonitrile (42.4 g), m.p. 124°-125° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.Br[CH2:15][CH2:16][CH3:17]>>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH2:9][N:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH:13]=2)[N:7]=1
Reactant: CNc1nc(-c2cccnc2)cs1
Reactant: CCCBr
Product: CCCN1CCC=C(c2csc(NC)n2)C1
Yield: 65 %

Procedure:
The procedure described in Example 1 was repeated, using the N-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and an excess of 1-bromopropane as the reactants. The title compound was purified by column chromatography (65% yield) and converted to its HCl salt by the procedure of Example 2. The resulting salt (mp 138° C.) contained 1.25 molecules of HCl and one molecule of water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].C(N(CC)CC)C>[Cu]I.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)O
Reactant: Fc1cc(I)ccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)C#Cc1ccnc(F)c1
Yield: 65.2 %

Procedure:
A solution of 2-fluoro-4-iodopyridine (3.0 g, 13 mmol), 3-butyn-2-ol (2.1 mL, 26 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.9 g, 1.3 mmol), copper (I) iodide (0.5 g, 2.6 mmol), triethylamine (5.4 mL 39 mmol), and anhydrous N,N-dimethylformamide (20 mL) were heated to 75° C. for 4 hours. When judged to be complete, the mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified using flash chromatography (4:1 hexanes:ethyl acetate) to provide 4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 66%) as an orange oil. 1H NMR (DMSO-d6): δ 8.21 (d, 1H), 7.32 (d, 1H), 7.20 (s, 1H), 5.62 (d, 1H), 4.61 (m, 1H), 1.36 (d, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17](=O)[CH3:18].CCOCC.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[S:14][CH:16]=[C:17]([CH3:18])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1csc2nc(SCc3ccccc3)nn12
Yield: 92.3 %

Procedure:
The product of stage (a) (22.3 g) and chloroacetone (9.6 g) were heated in ethanol (120 ml) under reflux for 22 hours. The solution was then reduced under vacuum, and the residue was stirred with a mixture of ether and aqueous sodium bicarbonate. The ether solution was separated, washed with water, dried over magnesium sulphate, and reduced under vacuum to give 24.1 g of the desired product as an orange oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:23]=[CH:24][CH:25]=[N:26]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:26][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Reaction time: 18 h
Yield: 81.7 %

Procedure:
3-Iodo-4-methylbenzoic acid (5 g, 19.1 mmol) and HATU (8.71 g, 22.9 mmol) in DMF (25 ml) were stirred at room temperature for 10 minutes. HOBT (2.58 g, 19.1 mmol), cyclopropylamine (1.37 g, 22.9 mmol) and DIPEA (2.5 ml, 57.3 mmol) were added and stirring continued for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (100 ml) and aqueous sodium carbonate (1M, 75 ml). The aqueous layer was extracted with DCM (50 ml) and the combined organic phases washed with brine (75 ml) and dried (magnesium sulphate). The solution was absorbed onto silica and purified by chromatography on silica eluting with ethyl acetate/cyclohexane (1:3). The product fractions were reduced to dryness under vacuum to give N-cyclopropyl-3-iodo-4-methylbenzamide (4.7 g, 82%). LCMS: retention time 3.09 min, MH+302.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.C(O)C>C(O)(=O)C.[Pt]=O>[CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl [(1S)-1-methyl-2-(pyridin-4-yloxy)ethyl]carbamate (1.03 g) in acetic acid (10 mL)/ethanol (10 mL) was added platinum oxide (500 mg), and the reaction mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in 0.5 M hydrochloric acid, and the solution was washed with ethyl acetate, basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (805 mg).