Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](Cl)=[N:15][OH:16].O>O1CCCC1>[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](=[N:15][OH:16])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(C(Cl)=NO)c(F)c1I
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(=NO)c2ccc(C)c(I)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
4-Methoxybenzylamine (2.00 mL, 15.2 mmol) was added dropwise to a solution of 2-fluoro-N-hydroxy-3-iodo-4-methylbenzimidoyl chloride (WO2006094187, 1.46 g, 4.7 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give a semi-solid. The solid was triturated with a hexanes/diethyl ether mixture and the solid was filtered and dried to give the title compound (1.66 g, 86%) as a white solid.
Reaction SMILES: [Mg].BrCCCCOCC1C=CC=CC=1.[Cu](C#N)C#N.F[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH:32]([C:36]2[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=2)C2OC2)C2OC2)=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:27]([O:31][CH2:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1ccc(C(OC(c2ccc(F)cc2)C2CO2)C2CO2)cc1
Agent: N#C[Cu]C#N
Agent: BrCCCCOCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-benzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:34])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:15]=3)[C@H:10]([CH3:33])[CH2:9]2)=[N:6][CH:7]=1.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[C:4]([Cl:34])=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=4)[CH2:9][C@H:10]3[CH3:33])[CH:19]=2)=[CH:21][CH:22]=1
Reactant: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H]1CN(c2ncc(C#N)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(5-bromo-3-chloro-pyridin-2-yl)-2-(R)-methyl-piperazin-1-y]-6-(4-fluoro-phenyl)-2-(2-(S)-methyl-pyrrolidin-1-yl)pyrimidine (700 mg) and Zn(CN)2 (94 mg) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[S:8]1[CH2:11][CH:10]([S:12][CH2:13][CH2:14][OH:15])[CH2:9]1.C[S:17](Cl)(=O)=O>ClCCl>[C:6]([O:15][CH2:14][CH2:13][S:12][CH:10]1[CH2:11][S:8][CH2:9]1)(=[S:17])[CH3:7]
Reactant: OCCSC1CSC1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(=S)OCCSC1CSC1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triethylamine (Et3N) (18 g) was added to a dichloromethane (130 ml) solution of 2-(3-thietanylthio)ethanol (21 g). A dichloromethane (30 ml) solution of methanesulfonyl chloride (MsCl) (18 g) was added dropwise to the mixture under cooling (−15 degrees centigrade), and the reaction was carried out at 0 degree centigrade for 1 hour. Coldwater was added to the reaction mixture for partition, and then the organic layer (dichloromethane solution) was added dropwise to a methanol (200 ml) solution of potassium thioacetate (AcSK) (21 g) under cooling (5 degrees centigrade), and the reaction was carried out for 10 hours. Ethyl acetate and water were added to the reaction mixture for carrying out extraction. The organic layer was washed with water and dried with magnesium sulfate. The resultant was filtered and then concentrated under reduced pressure to obtain a desired oily product (27 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:30]4/[C:29](=[O:37])[NH:28][C:36]5[C:31]/4=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:15][CH:16]=3)[N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a solution of (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (927 mg, 2.44 mmol), oxindole (325 mg, 2.44 mmol) and MeOH (20 mL) was added piperidine (24 uL, 0.244 mmol) and the reaction heated to 60° C. for 4 hours. A yellow precipitate crashed out of the reaction medium which was filtered and washed with MeOH to give the title compound (960 mg, 79%) as a yellow solid. MS ESI 495.3 [M+H]+, calcd for [C29H30N4O2Si+H]+ 495.22.
Reaction SMILES: [CH3:1][I:2].[N:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>ClC1C=CC=CC=1>[I-:2].[OH:25][C:24]1[C:15]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][N+:3]2([CH3:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:14])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CI
Reactant: O=C(NCCCN1CCOCC1)c1cc2ccccc2cc1O
Solvent: Clc1ccccc1
Product: C[N+]1(CCCNC(=O)c2cc3ccccc3cc2O)CCOCC1
Product: [I-]
Yield: 68.3 %

Procedure:
6.2 g of methyl iodide were added dropwise at 80° C. to a solution of 12.6 g of 3-hydroxynaphthalene-2-carboxylic acid (3-morpholin-4-ylpropyl)amide (RN 10155-47-2) in 60 ml of chlorobenzene. After refluxing for 4 hours, the suspension was cooled, filtered on a sinter funnel and spin-filtered. The white precipitate was washed with 20 ml of chlorobenzene and then with 20 ml of petroleum ether. The precipitate was then dried under vacuum. 12.5 g of a white solid of 4-{3-[(3-hydroxynaphthalene-2-carbonyl)amino]propyl}-4-methylmorpholin-4-ium iodide were obtained in a yield of 69%, melting at a temperature above 260° C. (Kofler) and the elemental analysis of which, calculated for C19H25N2O3.I, was:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:22])=[O:30]
Reactant: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 21.6 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile (0.068 g, 0.213 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.427 mmol) were combined in THF (6 mL) and treated with HATU (0.089 g, 0.235 mmol) at 25° C. overnight. The reaction mixture was concentrated to dryness and partitioned between DCM and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.0205 g, 0.046 mmol, 21.49% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br. s., 1H), 8.23 (br. s., 1H), 7.77 (s, 1H), 7.43-7.55 (m, 2H), 7.36 (t, J=7.71 Hz, 1H), 7.24 (br. s., 1H), 7.13 (br. s., 1H), 4.54 (d, J=4.99 Hz, 2H), 2.95 (spt, 1H), 1.18 (d, J=6.96 Hz, 6H). LC-MS (ES−) m/z 445.09, 447.18 [M−1]. LC-MS (ES+) m/z 447.08, 449.06 [M+H].
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)[C:43]([Cl:45])=O.[Cl:48]C(C1C=CC(Cl)=CC=1)CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:45][C:43]1[CH:2]=[C:24]([Cl:48])[CH:23]=[CH:22][C:21]=1[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:13]=1)=[O:7]
Reactant: NCC(Cl)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.23 cm3 of 2,4-dichlorophenylethylamine and 0.19 cm3 of triethylamine, 0.23 g of N-[2-(2,4-dichlorophenyl)ethyl]-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 202° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:27][CH2:26][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=3.C(O)C.Cl>[Pt]=O.O>[F:25][C:22]([F:23])([F:24])[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]1[CH2:26][CH2:27][N:9]([CH2:8][CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[CH2:10][CH:11]1[C:20](=[O:21])[NH:19]2
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccccn3)CC12
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCC3CCCCN3)CC12

Procedure:
A mixture of 5 g. (0.014 mole) of 2,3,4,4a-tetrahydro-3-[2-(2-pyridinyl)ethyl]-8-(trifluoromethyl)-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 60 ml. of ethanol, 120 ml. of water, 12 ml. of concentrated hydrogen chloride and 1 g. of platinum oxide catalyst is hydrogenated in a Parr apparatus for 2 hours. The catalyst is filtered and the solvents removed. The residue was crystallized from ethanol and recrystallized from methanol to yield 4.5 g. of the title compound as the dihydrochloride salt, m.p. 283°-286° C. (dec.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>[N+](C)([O-])=O>[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][Cl:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(=O)N1CCc2ccccc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)N1CCc2ccc(C(=O)CCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Aluminum chloride (2.9 g, 21.7 mmol) was added little by little to a mixture of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2 g, 10.5 mmol) and 4-chlorobutyryl chloride (1.56 g, 11 mmol) in nitromethane (5 ml) at room temperature and stirred for 2 hours at room temperature. The reaction solution was poured into ice water which was then extracted with ethyl acetate, washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-chloro-1-butanone (2.9 g) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:24]2[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25]2)[NH:12][C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:28][C:26]1([CH3:29])[CH2:25][CH:24]([CH:11]([NH:12][C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=2)[CH2:27]1
Reactant: CCOC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Temperature: 50 °C
Yield: 91.5 %

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (Intermediate 25) (43 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M NaOH (2 mL) was added. This was stirred at 50° C. at first as a suspension then as a clear solution for 4 h before cooling to room temperature. 1 N HCl was added until the solution was pH 5. This was extracted twice with ethyl acetate and the combined organics were dried over MgSO4. The solution was concentrated in vacuo to give (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (37.7 mg) as a white solid. MS (M+1): 375.1.
Reaction SMILES: CS[C:3](SC)=[C:4](C(OC)=O)[C:5]#[N:6].CC1N=CNC=1CSCCN.[C:24]([C:28]([C:43]#[N:44])=[C:29](SC)[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25].C(N)C#C>>[C:24]([C:28]([C:43]#[N:44])=[C:29]([NH:6][CH2:5][C:4]#[CH:3])[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C#N)=C(NCCSCc1[nH]cnc1C)SC
Reactant: COC(=O)C(C#N)=C(SC)SC
Agent: C#CCN
Agent: Cc1nc[nH]c1CSCCN
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C(=O)OC

Procedure:
When 1,1-bis(methylthio)-2-carbomethoxy-2-cyanoethylene [prepared according to the procedure described in Chem. Ber., 95, 2861 (1962)] is reacted with 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine according to the procedure of Example 6, Step A, and the resultant 1-carbomethoxy-1-cyano-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)-methylthio]ethylamino}ethylene treated with propargylamine by the procedure of Example 6, Step B, there is produced 1-carbomethoxy-1-cyano-2-(2-propynylamino)-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ncc(OC[C@@H]2CCN2)cc1Br
Reaction time: 0.5 h

Procedure:
To 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 66a (360 mg, 0.95 mmol) was added TFA in CH2Cl2 at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH:NH4OH 10:1:0.1 to afford to give the free base of the title compound. The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound (224 mg). mp 168-169° C. MS (CI/NH3) m/z 277/279 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.91-4.99 (m, 1H), 7.94 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H). Anal. Calcd for C9H10N2OBrCl.0.9 HCl: C, 34.83; H, 3.54; N, 9.03. Found: C, 34.85; H, 3.56; N, 8.82. [α]25D=−4.81° (c 0.13, MeOH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([N-:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[O:17])#[N:14].N1CCCCC1.Cl>C(O)C.O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)/[C:13]#[N:14])=[O:17]
Reactant: COc1ccc(C[N-]C(=O)CC#N)cc1OC
Reactant: O=CC=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(CNC(=O)/C(C#N)=C/C=C/c2ccc(O)c(O)c2)cc1OC
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) and N-(cyanoacetyl)3,4-dimethoxybenzylamide (47 mg, 0.2 mmol) in 8 mL of ethanol 40 μl of piperidine was added and the mixture was kept at room temperature for 1 h. 2N HCl and water were added and the precipitated solid was recrystallized from ethanol-water to give 52 mg (68%) of an orange solid. The product gave the following analytical data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5([OH:32])[CH2:29][C:28]([F:31])([F:30])[CH2:27]5)=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)[P:39]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(C)C.N1C=NC=N1.[OH:64]O>ClCCCl.C(Cl)Cl>[P:39]([O:32][C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][C:20]=2[O:33][CH3:34])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:64]
Reactant: OO
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: c1nc[nH]n1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(OP(=O)(OCc2ccccc2)OCc2ccccc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphen-yl)thieno[3,2-d]pyrimidin-4(3H)-one (1.01 g, 2.000 mmol) described in Example 2, dibenzyl diisopropylphosphoramidite (2.073 g, 6.00 mmol) and 1H-1,2,4-triazole (0.414 g, 6.00 mmol) in 1,2-dichloroethane (30 mL) was heated at reflux temperature. After 1 h, the mixture was cooled to RT; whereupon, 2 mL 50% H2O2 was added. After stirring for 15 minutes at RT, the mixture was diluted with CH2Cl2, washed sequentially with water, 5% aq. sodium thiosulfate and water. The organic layer was dried over MgSO4, concentrated and the crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford dibenzyl 1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl phosphate (1.3 g, 1.699 mmol, 85% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2H, d, J=8.56 Hz), 7.28-7.40 (10 H, m), 6.95 (1 H, d, J=8.56 Hz), 6.92 (1 H, d, J=2.27 Hz), 6.87 (1 H, dd, J=8.31, 2.27 Hz), 5.08 (4 H, dd, J=7.81, 1.26 Hz), 4.32 (2 H, s), 3.76 (3 H, s), 2.89-3.30 (4 H, m).
Reaction SMILES: [C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20][C:21]1([CH3:30])[CH2:26]C(O)[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1>C(O[Sn](CCCC)(CCCC)O[Sn](OC(=O)C)(CCCC)CCCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22][C:21]([CH3:30])([CH3:26])[CH2:20]1)=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCC(=O)NCCCCCC(=O)OC
Agent: CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)NCCCCCC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 110 °C
Yield: 89.6 %

Procedure:
A 250 mL single-necked reaction flask was equipped with a magnetic stirrer and a Dean-Stark trap fitted with a condenser and nitrogen inlet/outlet. To this flask was charged 6.1 g (22.5 mmol) of compound D, 5.29 g (33.7 mmol) of 2,2,6,6-tetramethyl-4-piperidinol, and 150 mL of toluene. Under a slow nitrogen flow, 8 mL of toluene was distilled off and the trap drained. After lowering the heat source and allowing the mixture to cool to 110° C., 0.17 g (0.28 mmol) of 1,3-diacetoxy-1,1,3,3-tetrabutyldistannoxane was added and the heat source raised. Another 100 mL of toluene was slowly distilled off over 16 hours and the resulting mixture was cooled to room temperature and diluted with methylene chloride. The organic solution was washed with water to remove excess amino alcohol and dried over anhydrous sodium carbonate. Filtration and removal of solvent under reduced pressure followed by further solvent removal in vacuo (<1 mm) at 60° C. gave 8.0 g (90%) of Compound VI as a light brown wax. The structure of the material was confirmed by 1H NMR analysis. 1H NMR (CDCl3): δ5.60 (m, 1H, NHCO—); 5.18 (m, 1H, R2CHOCO—); 3.25 (dt, 2H, —CH2—NH—); 2.28 (t, 2H, —CH2COO—); 2.16 (t, 2H, —CH2CONH—); 1.95-1.10 (m, 20H, CH2(CH2)3CH2, CH2(CH2)5, CH2CH2C(CH3)2); 1.20 (d, 12H, CH2C(CH3)2; 0.88 (t, 3H, —CH2CH3).