Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([N:6](C)[C:7](=S)[NH:8][NH2:9])CCCC1.[Cl:12][CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[CH2:23](O)[CH3:24]>>[ClH:12].[CH:24]1([CH2:23][NH:6][C:7]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[NH:9][N:8]=2)[CH2:21][CH2:19][CH2:13][CH2:14]1
Reactant: CCO
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CN(C(=S)NN)C1CCCC1
Agent: Cl
Product: CCOC(=O)c1c(NCC2CCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred slurry of 8.4 g (0.049 mole) of 4-cyclopentyl-4-methyl-3-thiosemicarbazide in 50 mL of absolute ethanol was treated with 8.1 g (0.049 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 18 hr, treated with 25 mL of 2N ethanolic hydrogen chloride and heated at reflux for 2 hr. The hot solution was filtered to remove amorphous sulfur and concentrated to a red oil which gave a crude solid product when triturated with acetone. After four recrystallizations, methyl ethyl ketone/2-propyl ether (twice), acetonitrile/acetone and finally from acetonitrile, there was obtained 3.2 g of crystalline product, mp 144°-146° C., as the hydrochloride salt.
Reaction SMILES: [CH2:1]=O.Cl.[CH2:4]([NH:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[P:16]([O-])([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>O1CCOCC1>[CH2:4]([N:11]([CH2:1][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][Cl:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: CCOP(=O)([O-])OCC
Reactant: ClCCCNCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(=O)(CN(CCCCl)Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1.6 mL of 37% aqueous formaldehyde solution is added to a suspension of N-benzyl-3-chloropropan-1-amine hydrochloride (7.9 g or 35.9 mmol) in dioxane (60 mL), the resulting mixture is slightly heated until it becomes a solution. The solution is cooled to room temperature, 3.2 mL of diethyl phosphate is added thereto, stirring at room temperature for 30 min, and then stirring at 90-100° C. for 3 h, the reaction is completed. The solvent is removed under reduced pressure, and the residue is purified by column chromatography (eluent: 1-4% MeOH in DCM) to obtain 7.6 g target compound (yield: 63%). The analytical data of the obtained product are as follows: 1HNMR (400 MHz, DMSO-d6): δ=7.30-7.21 (m, 5H), 4.01-3.93 (m, 4H), 3.69 (s, 2H), 3.59 (t, J=6.8 Hz, 2H), 2.83 (d, J=10.0 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 1.85-1.82 (m, 2H), 1.2 (t, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:15](N(OC)C)=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].O1CCC[CH2:30]1.C[Li]>C(OCC)C>[C:15]([C:5]1[S:6][C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)=[C:3]([C:1]#[N:2])[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])(=[O:16])[CH3:30]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame dried flask were placed 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)-N-methoxy-N-methylthiophene-2-carboxamide (1.45 g, 3.32 mmol) and tetrahydrofuran (90 mL, 1000 mmol) under argon. The solution was cooled to −78° C. and Methyllithium (4.653 mmol, 4.653 mmol) in diethylether (1.6M) solution was added. After addition, the mixture was kept at this temperature for 30 min. The mixture was quenched by ammonium chloride solution. The mixture was extracted with EtOAc and the organic layer was collected and dried over Na2SO4. The solvent was evaporated and the residue was purified using column chromatography. The title compound was collected as a white solid (0.93 g, 71.5%). LCMS: (FA) ES+391, 393. 1H NMR (400 MHz, d1-chloroform) δ: 8.43 (1H, d, J=5.28 Hz), 7.67-7.62 (2H, m), 7.48 (1H, dd, J=8.24, 2.01 Hz), 7.38 (1H, s), 7.35 (1H, d, J=8.24 Hz), 2.13 (3H, s)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])=[CH:3][N:2]=1.[CH3:18][O:19][C:20]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:21]=1[CH2:22][N:23]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:24]([C:27]1[CH:32]=[C:31]([I:33])[C:30](F)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH3:18][O:19][C:20]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:21]=1[CH2:22][N:23]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:24]([C:27]1[CH:28]=[CH:29][C:30]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[C:31]([I:33])[CH:32]=1)(=[O:25])=[O:26]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(I)c2)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(I)c2)c(OC)c1

Procedure:
The title compound was prepared according to Preparation 35 at 60° C. over 4 days using 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 30) and N-(2,4-dimethoxybenzyl)-4-fluoro-5-iodo-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 37) to give the product (420 mg, 43%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](OCC)(OCC)OCC.[CH3:15][C:16]1[CH:21]=[C:20]([NH2:22])[N:19]=[CH:18][C:17]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(=O)C.O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:17]1[CH:18]=[N:19][C:20]([N:22]2[CH:5]=[N:3][N:2]=[N:1]2)=[CH:21][C:16]=1[CH3:15])[CH3:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)Cc1cnc(N)cc1C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1cnc(-n2cnnn2)cc1C
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium azide (0.712 g, 11.0 mmol) was added to a stirred mixture of triethyl orthoformate (1.95 ml, 11.7 mmol) and ethyl (4-methyl-6-aminopyridin-3-yl)acetate (1.42 g, 7.30 mmol) in acetic acid (10 ml) and the mixture was stirred at 80° C. for 24 h. The reaction mixture was cooled, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to provide title compound. LC-MS (IE, m/z): 248 [M+1]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].ClCCl.O1CCCC1>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21]
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1N

Procedure:
(2S,3S)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt was prepared from (2S,3S)-3-t-butyloxycarbonylamino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Rob, et al., Bioorg. & Med. Chem. Lett. 1994, 4, 1789–1794) by treatment with a solution of trifluoroacetic acid-dichloromethane-tetrahydrofuran (1:10:10) at room temperature, followed by solvent evaporation and coevaporation with tetrahydrofuran under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[CH2:12][CH2:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[N:32]1([C:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:20][CH2:21]3)[CH2:12][CH2:13][CH3:14])[CH3:10])=[CH:4][CH:3]=2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1ccc(NC(=O)N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-[2-(4-aminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonyl-piperidin-4-ylmethyl)amine (60 mg) was dissolved in ethyl acetate (1 ml) and saturated potassium carbonate (1 ml). The mixture was cooled in an ice bath to 0° C. and morpholine-4-carbonyl chloride (0.03 ml) was added. After stirring for 30 minutes, the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed to give N-{2-[4-(morpholine-4-carbonylamino)phenyl]-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (90 mg) as a foam, M+H 481.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[C:12](O)(=O)C.[C:16]([C:19]1[N:27]=CC=[CH:24][C:20]=1[C:21](O)=O)(=O)[NH2:17]>C1(C)C=CC=CC=1>[C:16]([C:19]([NH:27][C:10]([C:2]1[N:1]=[CH:6][CH:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8])=[O:11])([CH3:12])[CH:20]([CH3:24])[CH3:21])#[N:17]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NC(=O)c1ncccc1C(=O)O
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C#N)NC(=O)c1ncccc1C(=O)O

Procedure:
The aminonitrile (1.108 mol) is added over a ten minute period to a stirred solution of 2,3-pyridinedicarboxylic anhydride (1.0 mol) containing acetic acid (2.0 mol) in toluene, while maintaining the temperature of the reaction mixture below 25° C. Upon completion of the aminonitrile addition the reaction mixture is stirred for one and one-half hrs and then weighed and analyzed by high performance liquid chromatography for the desired 2-carbamoyl nicotinic acid.
Reaction SMILES: [O:1]1[CH2:5][C@H:4]([OH:6])[C@@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.[C:11]1(C)[C:12]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=C[CH:23]=1>>[OH:6][C@H:4]1[C@H:3]2[O:7][CH2:8][C@H:9]([O:10][S:17]([C:12]3[CH:11]=[CH:16][C:15]([CH3:23])=[CH:14][CH:13]=3)(=[O:18])=[O:19])[C@H:2]2[O:1][CH2:5]1.[OH:6][C@@H:4]1[C@H:3]2[O:7][CH2:8][C@@H:9]([O:10][S:17]([C:12]3[CH:11]=[CH:16][C:15]([CH3:23])=[CH:14][CH:13]=3)(=[O:18])=[O:19])[C@H:2]2[O:1][CH2:5]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O[C@@H]1CO[C@@H]2[C@@H]1OC[C@@H]2O
Reactant: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3O)cc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1

Procedure:
A solution of 8.76 g of (3S,3aS,6R,6aR)-hexahydro-furo[3,2-b]furan-3,6-diol in 80 ml of pyridine is stirred for 16 hours with 13.7 g of toluenesulfonylchloride, solvent is distilled off and the distillation residue is dissolved in EtAc and extracted with 1N HCl, saturated aqueous NaHCO3-solution and H2O. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography. Toluene-4-sulfonic acid (3S,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (a) and toluene-4-sulfonic acid (3R,3aS,6S,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (b) are obtained. 1H-NMR(DMSO-d6) of form (a): 7.8 (d,2H,Ar—H,J=8.2 Hz), 7.5 (d,2H,Ar—H,J=8.6 Hz), 4.95 (d,1H,6-OH), 4.8 (m, 1H, H-3), 4.42 (dd,1H,H-6a,J=4.6 and 4.8 Hz), 4.38 (d,1H,H-3a,J=4.6), 4.08 (m,1H,H-6), 3.8 (m,2H,2×H-2), 3.7, 3.25 (2×dd, 2H, 2×H-5), 2.4 (s, 3H, Ar—CH3).
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:7]([OH:9])[CH3:8]>>[C:1](=[NH:6])([O:9][CH2:7][CH3:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C#N
Reactant: CCO
Product: CCOC(=N)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
Pivalonitrile (13 g, 157 mmol) was dissolved in absolute ethanol (50 mL) and cooled in a salt-ice bath. HCl gas was bubbled through this solution for 1 hr to saturate the solution. The reaction was warmed to RT. After 3 hr, the solvent was removed in vacuo to afford ethyl pivalimidate (16 g, 62%) as white solid. The crude ethyl pivalimidate (16 g, 97 mmol) was taken up in absolute ethanol (20 mL) and absolute ethanol saturated with ammonia (30 mL) was added. The reaction mixture was stirred at RT for 3 hr, whereupon ammonium chloride was filtered off and the salt washed with ethanol. The filtrate was concentrated in vacuo and the solid obtained was dried under vacuum to afford compound O.1, pivalimidamide (10 g, 76%). 1H NMR (DMSO-d6, 200 MHz): δ 8.6 (br s, 1H), 1.2 (s, 9H); MS m/z 101 [M+1]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:11]([C:21]1[NH:22][C:23]([CH:3]=[O:4])=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCc1ccc[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCc1ccc(C=O)[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To an ice cooled 4 g (56 mmol) of dimethylformamide was added 8.6 g (56 mmol) of phosphorous oxychloride over a period of 15 minutes while stirring under a nitrogen atmosphere. The mixture was stirred 15 minutes and then 15 mL of 1,2-dichloroethane was added. To this mixture was added a solution of 10.5 g (50.6 mmol) of 2-decylpyrrole, 35, in 15 mL of 1,2-dichloroethane while cooling in an ice bath. The reaction mixture was then heated under reflux for 15 minutes, during which time there was copious evolution of hydrogen chloride gas. After cooling to room temperature, a solution of sodium acetate trihydrate (38.1 g, 280 mmol) in 50 mL of water was added to the mixture. After heating at reflux for 15 minutes, the mixture was cooled and the 1,2-dichloroethane layer was separated. The aqueous layer was extracted with chloroform. The combined organic extracts were washed with saturated aqueous sodium carbonate solution and dried over anhydrous sodium carbonate. Following evaporation of solvent under vacuum, the crude product was purified by silica gel column chromatography with 1:9 ethyl acetate/hexanes as eluant, giving 9.8 g (82%) of compound 38 as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:6]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: BrCCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp, water (10 ml) and ethyl acetate (10 ml) were added. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo, giving 1.44 g of the crude material. The crude product was purified by flash chromatography (0–10% methanol in DCM), yielding 274 mg (23%) of the title compound 62. TLC (5% methanol in DCM): Rf=0.7. 1H-NMR (400 MHz, CDCl3): δ=7.88–7.83 (2H, m); 7.41–7.36 (2H, m); 4.91 (2H, t); 3.44 (2H, t); 2.66 (2H, m).
Reaction SMILES: [CH3:1][Mg]I.[C:4]([C:6]1[C:7]([C:22]([F:25])([F:24])[F:23])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]([CH3:20])[C:16](OC)=[O:17])[C:10]([CH3:21])=[CH:9]2)#[N:5].[NH4+].[Cl-].[CH3:28]C[O:30][CH2:31][CH3:32]>CCOC(C)=O>[CH3:21][C:10]1[N:11]([CH:15]([CH3:20])[C:16](=[O:17])[CH3:28])[C:12]2[C:8]([CH:9]=1)=[C:7]([C:22]([F:25])([F:24])[F:23])[C:6]([C:4]#[N:5])=[CH:14][CH:13]=2.[OH:30][C:31]([CH3:32])([CH3:1])[CH:15]([N:11]1[C:12]2[C:8](=[C:7]([C:22]([F:24])([F:23])[F:25])[C:6]([C:4]#[N:5])=[CH:14][CH:13]=2)[CH:9]=[C:10]1[CH3:21])[CH3:16]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reactant: C[Mg]I
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of methyl magnesium iodide (3M in Et2O) (0.322 ml, 0.967 mmol) in Et2O (1 mL) was added a solution of methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (Example 1) (0.100 g, 0.322 mmol) in Et2O (1 mL). The heterogeneous mixture was stirred in an ice bath for 5 min, at rt for 10 min, and then at 38° C. for ˜1 h. Upon cooling, the reaction mixture was diluted with EtOAc (5 mL) and treated with aq. saturated NH4Cl (5 mL). The mixture was partitioned between EtOAc (25 mL) and water (15 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel eluting sequentially with 50%, 75% and 100% CH2Cl2-hexanes to give 2-methyl-1-(1-methyl-2-oxopropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.008 g, 8% yield, less polar product) (MS (ESI): m/z 295 (MH+)) and 1-(2-hydroxy-1,2-dimethylpropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.069 g, 60% yield, more polar product) (MS (ESI): m/z 311 (MH+).
Reaction SMILES: [I-].C[C:3]1[N:4](CC=C)[C:5]2[C:12]([F:13])=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:10]([C:23]([O:25][CH3:26])=[O:24])=[CH:9][C:6]=2[N+:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1.O>ClCCl.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:13][C:12]1[C:5]2[N:4]=[CH:3][N:7]([CH3:8])[C:6]=2[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=CCn1c(C)[n+](C)c2cc(C(=O)OC)c(Nc3ccc(I)cc3F)c(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(I)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-allyl-4-fluoro-5-(2-fluoro-4-iodophenylamino)-6-methoxycarbony-1-methyl-3H-benzoimidazol-1-ium iodide, triphenyl phosphine (0.62 g, 2.5 mmoles), palladium tetrakis (0.47 g, 0.48 mmoles) in dichloromethane (15 ml) is cooled at −10° C. Pyrrolidine (0.65 ml) is added dropwise and the reaction mixture is stirred for 2 hours. Water is added and the mixture is extracted with dichloromethane. The organic phases are combined, washed with brine, dried Na2SO4 and concentrated under reduced pressure. The resulting solid is triturated with a mixture of Hexane/Ether (9/1) and isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].C[N+:13](C)(C)[CH2:14][C:15]1C=CC=C[CH:16]=1.C(#N)C=C.C(O)(=O)C>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][CH2:15][C:14]#[N:13])[CH:6]=[CH:5]2
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Cc1ccc2[nH]ccc2c1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: C=CC#N
Product: Cc1ccc2c(ccn2CCC#N)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
13 g (0.1 mol) of 5-methylindole are added to 4 ml of trimethylbenzylammonium hydroxide and 10 ml of acrylonitrile in 100 ml of dioxane while stirring. The mixture is then heated at 80° C. for 2 h and subsequently left to stand at room temperature for 3 days. Very dilute acetic acid is then added in order to neutralize the base. Extraction with EA (3×30 ml) is then carried out. The combined organic phases are dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed on SiO2 with DIP as eluent. Rf [DIP]=0.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[C:8]([CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O)(=O)[CH3:9].Cl.P(Cl)(Cl)([Cl:20])=O>CC1C=CC=CC=1>[Cl:20][CH2:14][CH2:15][C:11]1[C:12](=[O:13])[N:3]2[C:2]([CH3:1])=[CH:6][S:5][C:4]2=[N:7][C:8]=1[CH3:9]
Reactant: Cc1csc(N)n1
Reactant: CC(=O)C1CCOC1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc2scc(C)n2c(=O)c1CCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 40 parts of 4-methyl-2-thiazolamine, 30 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone and 225 parts of methylbenzene was stirred and refluxed for 2.50 hours with 0.6 parts of hydrochloric acid. After cooling to room temperature, 170 parts of phosphoryl chloride were added. The whole was heated slowly to about 110° C. and stirring was continued for 2 hours at this temperature. The reaction mixture was evaporated and the residue was poured onto crushed ice. Ammonium hydroxide was added till a pH of 8 was reached. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 19.3 parts of 6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one (intermediate 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16]C(O)=O)[CH:12]=[CH:13][CH:14]=1.S(Cl)(Cl)=O.C[N:25](C)[CH:26]=[O:27].[N-]=[N+]=[N-].[Na+]>O.O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[C:26](=[O:27])[NH:25][CH:16]=[CH:15]2
Reactant: COCCOCCOc1cccc(C=CC(=O)O)c1
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COCCOCCOc1ccc2c(=O)[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To 3-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}acrylic acid (10.7 g, 40.4 mmol) was added thionyl chloride (60 mL) and N,N-dimethylformamide (5 mL) and the reaction solution was refluxed under nitrogen atmosphere for 15 h. The reaction solution was dried, concentrated and the resulting oil was taken up in 1,4-dioxane (25 mL) and added dropwise during 15 min to a solution of sodium azide (7.87 g, 121 mmol) in water/dioxane (28 mL, 1:1) at 0° C. The suspension was stirred 30 min at 0° C., after which the precipitate was filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (3×150 mL) and the combined organic layer was washed with water (75 mL) and brine (75 mL), dried over sodium sulphate and filtered. The azide containing solution volume was reduced in vacuo, diphenyl ether (20 mL) was added and the remaining ethyl acetate was removed in vacuo. The diphenyl ether solution of the azide was added dropwise during 20 min to hot diphenyl ether (65 mL, 230° C.) and the obtained solution was heated 2 h at reflux (˜260° C.) and then left stirring at room temperature over night. Hexane was added to the reaction solution and the product precipitated out as a black oil. The oil was pre-absorbed on silica gel and purified by flash chromatography (solvent gradient:methanol/methylene chloride, 2:98→4:96) giving, after concentration and drying of the appropriate fractions, 3.4 g (32% yield) of the title compound as a yellow solid. MS (AP+) m/z 264 (M++1).