Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:11](OCC)(OCC)OCC.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[F:29]>C(Cl)Cl>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:11]=[C:5]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[CH:24][C:23]=1[F:29]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)c(F)c1
Reactant: COC(=O)CC(=O)C1CC1
Solvent: ClCCl
Product: COC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)C1CC1
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A stirred mixture of methyl 3-cyclopropyl-3-oxopropanoate (3.49 g, 26.3 mmol), triethyl orthoformate (5.2 mL, 31.6 mmol), and 4-bromo-3-fluoroaniline (4.47 g, 26.0 mmol) was heated at 140° C. overnight with a Dean Stark trap. After this time the reaction was cooled to room temperature, diluted with methylene chloride and filtered through a pad of silica. The filtrate was concentrated to afford the desired product (7.5 g, 85%) as a light yellow solid: ESI MS m/z 343 [C14H13BrFNO3+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:5]=1.Cl[CH2:27][C:28]1([CH2:31]C)[CH2:30][O:29]1.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH2:27][C:28]3([CH3:31])[CH2:30][O:29]3)[CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][N:17]=2)[CH:5]=1
Reactant: CCC1(CCl)CO1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC3(C)CO3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (20.7 mg, 0.52 mmol) was added to a solution of 4-methyl-6-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (150 mg, 0.47 mmol) in DMF (2 mL). The mixture was stirred for ten minutes after which time 2-(chloromethyl)-2-ethyloxirane (150 mg, 1.41 mmol) was added. The mixture was stirred at room temperature for 2 h, water was added, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4-methyl-6-(1-((2-methyloxiran-2-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine. MS ESI calc'd. for C19H19F3N5O [M+H]+ 390. found 390.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[NH:11][C:10](=[O:16])[NH:9]2)=[CH:4][CH:3]=1.[CH3:17][O-].[Na+].CI>CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][S:12](=[O:15])(=[O:14])[N:11]([CH3:17])[C:10](=[O:16])[NH:9]2)=[CH:6][CH:7]=1
Reactant: O=C1NC(c2ccc(Cl)cc2)CS(=O)(=O)N1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CO
Product: CN1C(=O)NC(c2ccc(Cl)cc2)CS1(=O)=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Using a method similar to that described by A. Etienne et al. (Bull. Soc. Chim. Fr., 1974, 1395) 5-(4-chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one DE3 is treated with sodium methoxide (1 equivalent) in methanol. Add methyl iodide (1.2 equivalent) in DMF and allow to stir for 12 h. Pour the mixture into ice water and collect the precipitate of the title compound DE4.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: CC(C)(C)c1nc(N)sc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1nc(N)sc1N1CCCCC1
Yield: 79.3 %

Procedure:
A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%) as an yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH2:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: COc1ccc(CCN)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 45.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide (53.6 mg, 45.07%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].Cl.[NH2:44][CH2:45][CH2:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH2:37][NH:44][CH2:45][CH2:46][C:47](=[O:48])[N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([OH:7])=[O:6]
Reactant: NCCC(=O)N1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield following steps 5 and 6, using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride as the reactant amine MS: m/e 687.5 (MH+), 1.76 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.91 (s, 3H) 0.96 (s, 3H) 1.05 (s, 3H) 1.09 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.85-1.85 (m, 20H) 1.87-1.96 (m, 2H) 2.01 (dt, J=13.36, 6.74 Hz, 2H) 2.04-2.12 (m, 1H) 2.16 (dd, J=17.07, 6.53 Hz, 1H) 2.48-2.57 (m, 1H) 2.81 (t, J=6.02 Hz, 2H) 2.88 (d, J=12.80 Hz, 1H) 3.33-3.43 (m, 3H) 3.43-3.52 (m, 4H) 4.65 (s, 1H) 4.76 (d, J=1.25 Hz, 1H) 5.35 (dd, J=6.02, 1.51 Hz, 1H) 7.22 (t, J=7.53 Hz, 1H) 7.64 (dd, J=9.79, 1.25 Hz, 1H) 7.75 (dd, J=8.03, 1.51 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −113.36 (s, 1 F).
Reaction SMILES: C(OC(=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[CH3:39][Mg]Br.[Cl-].[NH4+].[O:44]1[CH2:48][CH2:47]CC1>CCCCCC.C(OCC)(=O)C.CO>[CH3:39][C:48]([OH:44])([CH3:47])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC4CCOCC4)c3[nH]2)S1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC4CCOCC4)c3[nH]2)S1
Reaction time: 1 h
Yield: 21 %

Procedure:
Ethyl(2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (400 mg) was dissolved in tetrahydrofuran (10 mL), methylmagnesium bromide (1M tetrahydrofuran solution, 3.6 mL) was added and the mixture was stirred under ice-cooling for 30 min, and then at room temperature for 1 hr. To the reaction solution was added methylmagnesium bromide (1M tetrahydrofuran solution, 1.4 mL), and the mixture was stirred at room temperature for 1 hr. Methylmagnesium bromide (1M tetrahydrofuran solution, 1.4 mL) was further added, and the mixture was stirred at room temperature for 1 hr. Methylmagnesium bromide (1M tetrahydrofuran solution, 1.4 mL) was further added, and the mixture was stirred at room temperature for 1 hr. Moreover, methylmagnesium bromide (1M tetrahydrofuran solution, 1.4 mL) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 20:80:0, volume ratio), then basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 10:90:0, volume ratio) to give the title compound as a yellow oil (81 mg, yield 21%). The obtained yellow oil was crystallized from diethyl ether-hexane and recrystallized from ethyl acetate-hexane to give pale-yellow crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:23]#[N:24])[CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8]1)C.C([O-])(=O)C.[NH4+:30]>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:9]2[CH2:10][CH2:11][C:12]3[NH:30][C:4](=[O:3])[CH:5]([C:23]#[N:24])[CH2:6][C:7]=3[CH2:8]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(C#N)CC1CC(Cc2ccc(OC)cc2)CCC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC2CCC3=C(C2)CC(C#N)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Cyano-3-[3-(4-methoxyphenyl)methyl-6-oxocyclohexanyl]propanoic acid ethyl ester (1 g) (prepared as described in Example 5(a)) in methanol (10 ml) was treated with ammonium acetate (2.2 g) and left to stir at room temperature for 2 hours. The reaction mixture was diluted with water and a solid crystallised out. The solid was mixed with water and methanol, and the methanol removed under reduced pressure. The mixture was extracted into ethyl acetate, dried (MgSO4), and solvent evaporated to give the title compound as the quarterhydrate, mp 158°-9° C.
Reaction SMILES: [C@@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C@@H:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCCc2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1,2,3,4-tetrahydro-1-naphthylamine (26.9 g.) is dissolved in 200 ml. of toluene and 36 g. of acetic anhydride is added while the temperature from the reaction exotherm is moderated at 50° C. to 60° C. with an ice-bath. The solution is heated to reflux for 0.5 hr. and then stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is washed well with ether. On drying, 26.1 g. of the title compound, m.p. 153° C. to 155° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].C(O)(=O)C.O>C1C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)CCC(C)=O
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-n2c(C)ccc2C)c1

Procedure:
The mixture of ethyl 3-aminobenzoate (2.0 g), hexane-2,5-dione (1.8 ml) and acetic acid (0.7 ml) in benzene (10.0 ml) was heated under reflux for 5 hours, while water was removed in a Dean-Stark apparatus. To the mixture was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with a brine, dried over magnesium sulfate and evaporated in vacuo to give ethyl 3-(2,5-dimethylpyrrol-1-yl)benzoate (2.9 g) as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:14]C1[N:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:14].[CH3:22][O:21][C:18]1[CH:17]=[N:16][C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:20][CH:19]=1
Reactant: COc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cnc(N2CCNCC2)nc1
Product: Cl
Temperature: 60 °C
Reaction time: 144 h
Yield: 51.5 %

Procedure:
1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy-pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6](I)[CH:5]=1.[CH2:16]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:17][C:18]#[CH:19]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([C:19]#[C:18][CH2:17][CH2:16][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:5]=1
Reactant: C#CCCOC1CCCCO1
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(C#CCCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 148.8 %

Procedure:
To a degassed solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (41.4 g, 130 mmol) in DMF (200 mL) and triethylamine (40 mL) were added PdCl2(PPh3)2 (3.99 g, 5.68 mmol) and copper (I) iodide (7.43 g, 39.0 mmol). A degassed solution of 2-but-3-ynyloxy-tetrahydro-pyran (30.1 g, 195 mmol) in DMF (100 mL) and triethylamine (20 mL) was added at 80° C. over a period of 1 hour under nitrogen. After the addition, the reaction mixture was stirred at 80° C. for 2 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The solid was filtered, and washed with ethyl acetate. The ethyl acetate solution was washed with brine, and dried over anhydrous Na2SO4. The organic phase was concentrated to dryness, to afford 66.8 g crude 4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acid methyl ester. This was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.O.NN.C1(=O)NC(=O)C2=CC=CC=C12>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:6][C:5]2[N:16]3[C:17]([CH2:33][NH2:34])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:23]([C:24]3[CH:25]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.33 h

Procedure:
A stirred mixture of 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (1.81 g, 0.003 mole) and absolute ethanol (30 ml) is treated with hydrazine hydrate (0.437 ml, 0.009 mole) and kept in an oil bath at 72°-76°C for two hours and 20 minutes. During this period the phthalimide dissolves and a second solid forms. The mixture is cooled in an ice bath and filtered. The solid is washed with ethanol and methylene chloride. The filtrate is concentrated in vacuo. This residue is mixed with cold water and extracted with chloroform. The extract is washed (brine), dried over anhydrous sodium sulfate and concentrated in vacuo to give 8-chloro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine as a crude oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:21]([C@H:23]([CH:33](O)[CH2:34][CH3:35])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:33]([CH2:34][CH3:35])[C@@H:23]([CH2:21][CH3:22])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: CCC(O)[C@@H](CC)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CNC(=O)OC(C)(C)C

Procedure:
2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (101 mg, 0.385 mmol), tert-butyl (2S)-2-ethyl-3-hydroxypentylcarbamate (89 mg, 0.385 mmol), PPh3 (151 mg, 0.577 mmol) and DEAD (90.9 μL, 0.577 mmol) were combined at ambient temperature in 5 mL anhydrous THF. The reaction mixture was heated at reflux for 6 hours. The crude mixture was cooled to ambient temperature and diluted with water and ethyl acetate. The crude mixture was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]2[CH:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]4[CH:3]=3)[CH:21]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Nc1nnc2cc(Br)ccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccn2c(NC(C)C)nnc2c1
Temperature: 150 °C
Yield: 141.7 %

Procedure:
In a microwave tube was placed 7-bromo-N-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.105 g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.16 g, 0.54 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.024 g, 0.034 mmol) and sodium carbonate monohydrate (0.29 g, 2.3 mmol) in 2.8 mL of DME and 1.1 mL of water. The mixture was heated in the microwave at 150° C. for 15 min. Water was then added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 203 mg of a black solid. The crude material was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound as a pale yellow solid. MS (ESI, pos. ion) m/z: 350.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:23][CH2:24][CH3:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH2:23][CH2:24][CH3:25])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Cl
Reactant: CCCC(=O)CC(=O)OC
Product: CCCC1=C(C(=O)OC)C(c2ccccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: O[CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([SH:44])[N:37]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([O:35][CH3:34])[N:37]=[C:38]([S:44][CH:2]([C:7]([O:20][CH3:21])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])[N:39]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine were added, and 3.2 g (28 mmol) of methane-sulfonyl chloride were added dropwise while stirring. The mixture was stirred at room temperature for 2 h., washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of DMF. After stirring at room temperature for 2 h. and at 60° C. for a further 2 h., the mixture was poured into 1 liter of ice-water, and the resulting precipitate was filtered off with suction. After drying, 3.19 g (29%) of a white powder remained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[NH2:13]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2c(c1)C(=O)NCC2
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a suspension of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (8.1 g, 50 mmol) in conc. HCl (100 mL) cooled in an ice-H2O bath was added a solution of NaNO2 (3.45 g, 50 mmol) in H2O dropwise at such a rate that the reaction mixture never rose above 5° C. After stirring for 30 min, to the resulting mixture was added a solution of SnCl2.2H2O (22.5 g, 0.1 mol) in conc. HCl (150 mL) dropwise at 0° C. in an ice-H2O bath. The resulting mixture was stirred for another 2 h at 0° C. The precipitate was collected by suction, washed with ether to afford 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.3 g), which was used for the next reaction without further purification.