Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1O)=[O:11])[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1[Cl:4])=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (54) (9.87 g, 27 mmol) in dry CH2Cl2 at 0° C. After adding anhydrous DMF (0.5 mL), the solution was allowed to come at room temperature and was further stirred at room temperature for 24 h. Excess solvent was evaporated to yield 7-chloro-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as off white solids. Yield 85%; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 5.36 (s, 2H), 6.88 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.53 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H ppm; MS m/z=378 amu (M++H).
Reaction SMILES: C(O[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C1C=CC=CC=1.[CH3:28][N:29](CC1C=CC(C(OCC)=O)=CN=1)[CH3:30].Cl.C(OCC)(=O)C=C>O=[Pt]=O>[CH3:28][N:29]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][N:11]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:30]
Reactant: CCOC(=O)c1ccc(CN(C)C)nc1
Reactant: CCOC(=O)CCN1CC(C(=O)OCC)CCC1COCc1ccccc1
Agent: O=[Pt]=O
Agent: C=CC(=O)OCC
Agent: Cl
Product: CCOC(=O)CCN1CC(C(=O)OCC)CCC1CN(C)C
Yield: 51 %

Procedure:
Using the same procedure employed for the preparation of 15c and using 14e (335 mg, 1.6 mmol), 2 M ethereal HCl (6 mL), PtO2 (24 mg), and ethyl acrylate (1.7 mL, 16 mmol) gave 15e (259 mg, 51%) and 17 (52 mg, 12%) following PTLC purification (10% MeOH—CHCl3). Compound 15e: reddish yellow oil; Rf 0.37 (10% MeOH—CHCl3); IR (neat) 2945, 2818, 1731, 1457, 1376, 1182 cm−1; 1H NMR (CDCl3) δ 1.18 (t, J=7.2 Hz, 3H, CH2CH3), 1.19 (t, J=7.2 Hz, 3H, CH2CH3), 1.56-1.70 (m, 4H, C(3)H2, C(4)H2), 2.15 (s, 6H, N(CH3)2), 2.26-2.48 (m, 5H, C(5)H, NCH2CH2, (CH3)2NCH2), 2.69-2.91 (m, 5H, C(2)H, C(6)H2, NCH2CH2), 4.05 (q, J=7.2 Hz, 2H, CH2CH3), 4.07 (q, J=7.2 Hz, 2H, CH2CH3), the 1H NMR assignments were consistent with the COSY spectrum; 13C NMR (CDCl3) 14.0 (CH2CH3), 14.1 (CH2CH3), 22.8 (C(3)), 25.5 (C(4)), 33.5 (NCH2CH2), 40.1 (C(5)), 46.0 (N(CH3)2), 49.3 (C(6)), 49.7 (NCH2CH2), 55.4 (C(2)), 57.7 ((CH3)2NCH2), 60.1 (2C, CH2CH3), 172.6 (C(O)), 174.2 (C(O)) ppm, the assignments were consistent with the DEPT and HMQC spectra; MS (+CI) 315 [M+1]+; Mr (+CI) 315.229 49 [M+1]+ (calcd for C16H31N2O4 315.228 38). Compound 17 (cis- and trans-mixture): Rf 0.75 (10% MeOH—CHCl3); 1H NMR (CDCl3) δ 1.00 (d, J=6.6 Hz, 2H), 1.10 (d, J=6.6 Hz, 1H), 1.21-1.28 (m, 6H), 1.44-2.00 (m, 4H), 2.21-2.30 (m, 1H), 2.42-2.59 (m, 4H), 2.67-2.88 (m, 3H), 4.08-4.17 (m, 4H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1cccs1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccs4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.620 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-thiophene-carbonyl chloride (0.3 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-thienylcarboxamide (0.35 g, 47%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.18 (t, J=5.8 Hz, 1H), 7.88-7.72 (m 5H), 7.20-7.17 (dd, J=3.9 and 4.7 Hz, 1H), 5.22-5.15 (dd, J=5.5 and 12.7 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.98-2.85 (m, 1H), 2.66-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.93, 161.52, 139.26, 139.14, 134.83, 133.14, 131.53, 131.11, 128.51, 127.96, 127.12, 121.93, 48.89, 38.09, 30.93, 21.99; Anal. Calcd. For C19H15N3O5S: C, 57.42; H, 3.80; N, 10.57. S, 8.07. Found: C, 57.80; H, 3.93; N, 10.22; S, 7.99.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(C)(O)CCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(O)CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (7 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-bromo-2-methylbutan-2-ol (243 mg, 1.456 mmol) (306 mg, 74%). ESI-MS m/z [M+H]+ calc'd for C14H21ClN4O2, 313.14. found 313.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[NH:36][N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=3)[C:31]=12>CN(C=O)C>[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=3)[C:31]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(O)c(F)c3)c12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(O)c(F)c1)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of compound (8) (200 mg, 0.502 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (2.0 mL) was added a solution of 4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol (see Table 1, below) (148 mg, 0.602 mmol) in DMF (2.0 mL) and the reaction mixture stirred at RT for 18 hr. The solvent was removed in vacuo and the crude material was purified by flash column chromatography, eluting with 5% methanol in DCM, to afford the title compound, Intermediate D (81 mg, 27%) as a off-white solid: m/z 606/608 (M+H)+ (ES+) (Method B).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[C:16]([F:24])[CH:15]=1.[Cl-].[NH4+].[O:27]1CCC[CH2:28]1>CN(C)C=O>[Br:13][C:14]1[C:15]([CH:28]=[O:27])=[C:16]([F:24])[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: COCOc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (364 μl) in tetrahydrofuran (1 ml) was cooled to −78° C., and thereto was added dropwise n-butyl lithium (0.86 ml, 2.77M hexane solution), and the mixture was stirred at 0° C. for 10 minutes. The reaction mixture was cooled to −78° C., and thereto was added dropwise a solution of 1-bromo-3-fluoro-4-(methoxymethoxy)benzene (470 mg) in tetrahydrofuran (1 ml), and the mixture was stirred for 30 minutes. To the mixture was added dropwise N,N-dimethyl-formamide (210 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (48 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14](=[O:18])[CH2:15][CH:16]=[CH2:17].C(N(CC)CC)C>C(O[Pd]OC(=O)C)(=O)C>[CH3:12][O:13][C:14](=[O:18])[CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2ccc(I)cc2s1
Reactant: C=CCC(=O)OC
Agent: CC(=O)O[Pd]OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C/C=C/c1ccc2nc(C)sc2c1
Temperature: 130 °C

Procedure:
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), but-3-enoic acid methyl ester (100 mg, 1.2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 mL) is heated in a microwave apparatus at 130° C. for 30 minutes. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give (E)-4-(2-methyl-benzothiazol-6-yl)-but-3-enoic acid methyl ester. MS 248.3 (M+1).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][NH:22][N:21]=1>O1CCCC1>[O:18]=[C:10]1[C:9](=[CH:8][NH:19][C:20]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][NH:22][N:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1n[nH]cc1C(=O)O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]cc1C(=O)O

Procedure:
The named compound is prepared by substituting 3-amino-1H-pyrazole-4-carboxylic acid for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1601 gms. of 3-amino-1H-pyrazole-4-carboxylic acid by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26][C@@H]5CCCN5C[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.C(OC([N:43]1[CH2:50][CH:49]2[CH:45](CNC2)[CH2:44]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:22][CH:49]5[CH:45]([CH2:44][NH:43][CH2:50]5)[CH2:26]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC5CNCC5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (34 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A solution of methyl 4-hydroxy-3-propylbenzoate (7.00 g, 36.0 mmol), benzyl bromide (11.48 g, 0.15 mol) and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (20 mL) was heated with stirring at 80° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 10.25 g of the title compound (yield: 100%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.C1(CN2C3C=C(F)C(F)=CC=3N=C2C2C=CC=CC=2OCC2C=CC(C3NN=NN=3)=CC=2F)CCCCC1.Br[CH2:77][C:78]1[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=1[F:86]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:77][C:78]3[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=3[F:86])[C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[N:12]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: Fc1cc2nc(-c3ccccc3OCc3ccc(-c4nnn[nH]4)cc3F)n(CC3CCCCC3)c2cc1F
Product: COc1cc(Cl)ccc1-c1nc2ccccc2n1Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-1H-benzoimidazole (Example 39, intermediate d) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Yellow solid (18%). MS (Turbo Spray): m/z=392.4 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29]N.S>C(O)C>[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CC(C)CCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (6 g) and 3-methylbutylamine (18.9 cc) in absolute ethanol (90 cc) is saturated with hydrogen sulphide and brought for 16 hours to a temperature in the region of 105° C. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily brown residue is purified by chromatography on a column (height: 40 cm; diameter: 4 cm) of silica gel (0.02-0.063 mm), eluting with methylene chloride (1 liter) and then with a mixture (95:5 by volume) (1.5 liters) of methylene chloride and methanol and collecting 80-cc fractions. Fractions 23 to 36 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (6.76 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH2:19](B(O)O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:5])[CH3:2]
Reactant: CCCCCCB(O)O
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), n-hexylboronic acid, sodium carbonate and POPd to give 3-cyano-4-hexyl-quinoline-6-carboxylic acid ethyl ester as a clear oil. LC-MS m/e 311 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC#Cc1cccc(CN2CCOCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 500-mL 1-necked round-bottom flask was equipped with a magnetic stirring bar and rubber septum with a nitrogen inlet. The vessel was charged with the product of Example 6 (13.6 g), dichloromethane (100 mL) and triethylamine (8.43 mL). The reaction mixture was cooled to 0° C. in an ice bath, and a solution of methanesulfonyl chloride (6.93 g) in dichloromethane (10 mL) was added in drops over 30 min. The cooling was removed and the reaction mixture was allowed to warm up to room temperature. After 1 h when TLC indicated complete conversion, 50 mL ice water was added, and the reaction mixture was transferred to a 500-mL separatory funnel. The organic extract was separated and washed with aqueous NaHCO3, brine, and dried over MgSO4. After filtration, the solvents were evaporated under reduced pressure (rotary evaporator, 30° C.) to obtain the title compound as pale yellow gum (17.5 g).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]([CH3:9])([CH3:8])[C:5]#[C:6][Cl:7].[C:10]1([O-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CN(C)C=O>[Cl:7][CH:6]=[C:5]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([CH3:9])([CH3:8])[C:3]#[CH:2]
Reactant: CC(C)(C#CCl)C=CCl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)C(=CCl)Oc1ccccc1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
163 g (1 mole) of 1,5-dichloro-3,3-dimethyl-pent-1-en-4-ine and 232 g (2 moles) of sodium phenolate in 1 liter of absolute N,N-dimethylformamide are heated to 140° C. in the course of 3 hours and stirring is then continued for 4 hours. The mixture is worked up as described for method A, giving 204 g of crude product, which after distillation (boiling point 0.15/87°-94° C.) gives 141 g (that is to say 64% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:22][C:19]3[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1

Procedure:
To a 25 mL round bottomed flask was added 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (0.7204 g, 3.828 mmol), 4-aminophenol (0.4254 g, 3.832 mmol), and cesium carbonate (1.6144 g, 4.593 mmol) in dimethyl sulfoxide at 90° C. Upon completion, the reaction was filtered through Celite™ and the filtrate was condensed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The organic extract was washed with water (3×15 mL), brine (3×15 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]([N:27]=[C:28]=[S:29])(=[O:26])[CH3:25]>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[S:29])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: CC(=O)N=C=S
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=S)NC(C)=O
Reaction time: 18 h
Yield: 54 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (1.2 g.; 0.0036 mole) in acetone (15 ml.) is added acetyl isothiocyanate (0.37 g.; 0.0036 mole). The reaction mixture is heated to reflux and then allowed to stand at room temperature for 18 hours. The product is collected by filtration, washed successively to afford 0.85 g. (54% yield) of 3-(3-carbomethoxythioureido)-4-(3-acetylthioureido)benzophenone, m.p. 210° C., dec.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.O>CN(C=O)C>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#CCCN1CCC(N)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NC2CCN(CCC#N)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.283 g, 2.800 mmol) and 3-(4-aminopiperidin-1-yl)propanenitrile (0.161 g, 1.050 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. Water was added and the mixture was extracted with EtOAc. The organic phase was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a mixture of heptane and EtOAc (20:80) to 100% EtOAc, then a mixture of MeOH and EtOAc (1:99) as eluant, to give the title compound (0.25 g, 89%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.51 (m, 2H), 7.49-7.44 (m, 3H), 5.20 (br d 1H), 4.46-4.38 (m, 1H), 3.01-2.91 (br m, 1H), 2.70-2.65 (br m, 2H), 2.55 (t, 2H), 2.41 (t 2H), 1.74-1.63 (m 4H), 1.60 (d 6H) 1.44-1.35 (m 2H); 13C NMR (125 MHz, CDCl3): δ 158.7, 134.5, 131.8, 130.1, 128.9, 125.3, 118.8, 106.8, 53.3, 51.5, 50.0, 47.8, 32.4, 20.4, 16.4: Mass Spectrum: M−H+ 403.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.[C:23]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH3:23])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: CO
Product: C#CC(C)(C)N1CCC(OC)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-methoxy-2(1H)-pyrimidinone.