Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:53][OH:54]>CN(C=O)C>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:19])[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a solution of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2.00 g, 6.25 mmol) and triethylamine (1.741 mL, 12.49 mmol) in DMF (15 mL) was added HATU (2.423 g, 6.37 mmol). The reaction was stirred at 23° C. for 5 min, then was added (S)-2-amino-3,3-dimethylbutan-1-ol (0.805 g, 6.87 mmol). The reaction was stirred at 23° C. for 1 h then concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.48 g). LCMS m/z=419.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=7.8, 4.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.46 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.6, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.93-4.01 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.37 (dd, J=5.3, 1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H) 8.28 (d, J=5.3 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[C:28]([O:27][C:25]([N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:24][C@H:19]1[CH3:18])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC1(C)CN(C(=O)CCl)c2cc(C#N)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(C#N)cc32)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 175.7 %

Procedure:
To a solution of 1-(2-chloroacetyl)-3,3-dimethylindoline-6-carbonitrile (0.10 g, 0.40 mmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.088 g, 0.41 mmol) in acetonitrile (1.5 mL) was added triethylamine (0.083 mL, 0.6 mmol). The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was then cooled and concentrated. The reaction was repeated on a 0.6 mmol scale and the combined crude material was purified by flash column chromatography, eluting with 20% EtOAc in heptane, to give the title compound (0.29 g) [M+H]+=413.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([Cl:15])([CH3:14])[CH3:13])[N:5]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([C:12]([Cl:15])([CH3:14])[CH3:13])[N:5]=1
Reactant: CSc1nc(N)nc(C(C)(C)Cl)n1
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Cl)c1nc(N)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Chlorine gas was passed at 20 to 25° C. into a suspension of 110 g of 2-amino-4-methylthio-6-(1-chloroisopropyl)-1,3,5-triazine in 0.75 l of glacial acetic acid (30 min). The reaction mixture was stirred for 30 min at approx. 20° C., sprayed with nitrogen gas for 1 h at room temperature, poured into 3.75 l of ice-cold aqueous solution of 260 g of sodium hydroxide and stirred for 5 min. After filtration with suction and drying, 83 g (80%) of 2-amino-4-chloro-6-(1-chloroisopropyl)-1,3,5-triazine were obtained as a white powder (m.p. 110° C.); 1H NMR (CDCl3): δ=1.9 (s, 6 H), 6.0 (s br., 2 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[F:44])(=O)C.C(OC1C=CC(C(CCNC2C=C(OC)C(OC)=CC=2[C@@H]2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1F)(=O)C>>[CH2:1]([N:3]([C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([OH:34])=[C:36]([F:44])[CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1F
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: COc1cc(NCCC(=O)c2ccc(OC(C)=O)c(F)c2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-acetoxy-3-fluorobenzoic acid according to an analogous synthetic method to Preparation Example 154, pivalic acid (R)-6-{2-[(4-acetoxy-3-fluorobenzoyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (537 mg) was used according to an analogous synthetic method to Preparation Example 155 to provide the title compound (298 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH:12]([C:17](O)=[O:18])[CH2:11][CH2:10][C:9]2=1)(=[O:3])[NH2:2].ClC(OCC(C)C)=O.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1.O.C(Cl)Cl>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:27])[C:20]=1[C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:16]2[C:8]=1[C:9]1[CH2:10][CH2:11][CH:12]([C:17]([N:38]([O:39][CH3:40])[CH3:37])=[O:18])[CH2:13][C:14]=1[NH:15]2
Reactant: CNOC
Reactant: NC(=O)c1ccc(-c2c(F)cccc2F)c2c3c([nH]c12)CC(C(=O)O)CC3
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A solution of 8-carbamoyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid (Intermediate 23-3, 720 mg, 1.944 mmol) and TEA (1.084 mL, 7.78 mmol) in THF (5 mL) was treated with isobutyl chloroformate (266 mg, 1.944 mmol) at 0° C. After stirring for 10 min, a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (190 mg, 1.944 mmol) in THF (2 mL) and water (0.5 mL) was added. The mixture was stirred for 30 min, then diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc) to provide 5-(2,6-difluorophenyl)-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide as a white solid (802 mg, 93%). 1H NMR (400 MHz, chloroform-d) ε1.70-1.82 (m, 1H) 1.90-1.99 (m, 1H) 2.19-2.25 (m, 2H) 2.32-2.42 (m, 1H) 2.84-2.92 (m, 1H) 3.05-3.19 (m, 1H) 3.23 (s, 3H) 3.70 (s, 3H) 6.98-7.06 (m, 3H) 7.35-7.42 (m, 2H) 10.10 (s, 1H). Mass spectrum m/z 414.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2ncc(Br)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.0 g, 14.1 mmol) in a mixture of N,N-dimethylformamide and tetrahydrofuran (30 mL, 2:1) at 0° C. was added 60% sodium hydride in mineral oil (0.68 g, 17.0 mmol) and the reaction mixture was stirred for 30 minutes, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.7 mL, 14.9 mmol). The reaction mixture was stirred for 16 hours at room temperature then it was quenched by the careful addition of water and diluted with ethyl acetate (250 mL), washed with brine (3×150 mL), dried over sodium sulfate, filtered and concentrated. Gradient column chromatography (10% to 30% ethyl acetate in hexane) provided 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (4.4 g, 92%). 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 8.12 (s, 1H), 5.67 (s, 2H), 3.62 (m, 2H), 2.76 (s, 3H), 0.96 (m, 2H), 0.00 (s, 9H). MS (EI) for C13H20BrN3OSi: 342, 344 (MH+, Br iotope pattern).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 2.3 g (10 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.06 g (15 mmol) of iodobenzene, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetonitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg (0.5 mmol), was then added and stirring under argon was continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and evaporated. The crude product was chromatographed over 100 g of silica gel (Merck 70-230 mesh) using methylene chloride for elution. The clean fractions were combined and evaporated and the residue was crystallized from hexane to yield 2.1 g (68%) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-(phenylethynyl)-2H-1-benzopyran-6-ol with m.p. 109°-111° C. The analytical sample was recrystallized from hexane and had m.p. 111°-113° C. Anal. Calcd. for C21H22O2 : C, 82.32; H, 7.24 Found: C, 82.02; H, 7.30
Reaction SMILES: CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.Cl[C:42]1[CH:51]=[C:50]2[C:45]([C:46]([N:52]3[CH2:56][CH2:55][CH2:54][CH2:53]3)=[N:47][CH:48]=[N:49]2)=[CH:44][CH:43]=1.[N:57]1([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[N:52]1([C:46]2[C:45]3[C:50](=[CH:51][C:42]([N:60]4[CH2:59][CH2:58][N:57]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61]4)=[CH:43][CH:44]=3)[N:49]=[CH:48][N:47]=2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2c(N3CCCC3)ncnc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(N4CCCC4)ncnc3c2)CC1
Temperature: 100 °C

Procedure:
Potassium tert-butoxide (998 mg, 8.99 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropyl-biphenyl (X-Phos) (79 mg, 0.18 mmol) and tris-(dibenzylideneacetone)-dipalladium [Pd2(dba)3] (36 mg, 0.036 mmol) were added, under nitrogen, to a mixture of 7-chloro-4-(pyrrolidin-1-yl)quinazoline (A) (840 mg, 3.59 mmol) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.39 mmol) in toluene (49 ml). The reaction mixture was then heated for 15 h at 100° C. The reaction mixture was cooled to room temperature, and water (25 ml) and ethyl acetate (25 ml) were added. The aqueous phase was extracted with ethyl acetate (2×25 ml), and the combined organic phases were washed with saturated sodium chloride solution (20 ml). The organic phase was then dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/-dichloromethane/ammonia solution (25% aq.) (50:10:0.5) and ethyl acetate/dichloro-methane/methyl tert-butyl ether/ammonia solution (25% aq.) (50:10:10:0.7).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[C:25]([F:26])=[CH:24][C:23]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:22][C:21]=2[F:31])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[F:31][C:21]1[CH:22]=[C:23]([C:27]([OH:30])([CH3:29])[CH3:28])[CH:24]=[C:25]([F:26])[C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCc1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-(6-bromopyridin-2-yl)ethanol (48 mg, 0.24 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (75 mg, 0.24 mmol) as the starting materials.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]1=[O:15].[Br:16]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3](=[O:15])[N:2]2[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)n(C)c(=O)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1Br)n(C)c(=O)c(=O)n2C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (0.66 g, 3.2 mmol) in acetic acid (40 mL) was added bromine (0.52 g, 3.2 mmol) and the solution stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and poured into water. The solution was neutralized with aqueous NaOH to Ph=7, extracted with dichloromethane and washed with brine, dried (MgSO4), filtered and evaporated to give 0.9 g of 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 2.47 (s, 3 H), 3.64 (s, 6 H), 7.09 (s, 1 H), 7.40 (s, 1 H).
Reaction SMILES: CO[C:3]([CH:5]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([C:21]#[N:22])[CH2:6]1)=[O:4].[NH2:23][NH2:24].[Cl-].[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[C:21]([N:7]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[CH:11][NH:12]4)=[CH:19][CH:5]([C:3]([NH:23][NH2:24])=[O:4])[CH2:6]1)#[N:22]
Reactant: NN
Reactant: COC(=O)C1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CN1CC(C(=O)NN)C=C2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
950 mg of 6-cyano-9,10-didehydroergolinecarboxylic acid methyl ester (3.2 mmol) is dissolved in 100 ml of chloroform and 18 ml of anhydrous hydrazine and stirred for one hour in an ice bath and for 3 hours at room temperature. The mixture is distributed between saturated sodium chloride solution and methylene chloride; the organic phase is washed with water, dried with magnesium sulfate, and evaporated (crude product 739 mg). The product is chromatographed on silica gel with methylene chloride, ethyl acetate, and methanol, yielding the pure 6-cyano-9,10-didehydroergolinecarboxylic acid hydrazide. A solution of 950 mg (3.2 mmol) of this hydrazide in 100 ml of tetrahydrofuran is cooled in an ice bath and combined in succession with 11 ml of a saturated solution of hydrogen chloride in toluene (about 0.7N), 3.5 ml of a 1N lithium nitrite solution in tetrahydrofuran, and 22 ml of the above hydrogen chloride solution. Under ice cooling, the mixture is agitated for 20 minutes, then diluted with 140 ml of dioxane, and heated for 30 minutes in an oil bath preheated to 80° C. After cooling in an ice bath, 20 ml of 0.2N hydrochloric acid is added thereto, the mixture is allowed to stand for 20 minutes and evaporated to dryness. The residue is made into a solution with a small amount of methanol, distributed between chloroform and sodium bicarbonate, the aqueous phase is washed with chloroform, the organic phase respectively several times with water, dried with magnesium sulfate, and evaporated. 1.0 g of the crude 8-amino-6-cyano-9,10-didehydroergoline is dissolved in 15 ml of pyridine, combined with 0.6 ml of acetyl chloride, and ice is added after one hour; the mixture is distributed between saturated bicarbonate solution and methylene chloride; the organic phase is dried and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][N:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7]1=O)=[O:5])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)=O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][N:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1=O
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)C1=C(Nc2ccccc2)CN(C(=O)c2ccccc2)C1

Procedure:
A mixture of 100 g of 1-benzoyl-3-oxopyrrolidin-4-carboxylic acid ethyl ester, 42 ml of aniline and 23 ml of formic acid in 1.2 liters of ethanol is heated to reflux for 15 hours, concentrated by evaporation and the residue is crystallised from the ether/methylene chloride. 3-Anilino-1-benzoyl-2,5-dihydro-1H-pyrrol-4-carboxylic acid ethyl ester is obtained. M.P. 149°-151°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[N:14]2[N:15]=[CH:16][C:17]3[C:22]([C:13]2=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]=1[C:29](OCC)=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:9])[CH3:8]>C(OCC)C>[OH:30][CH2:29][C:11]1[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[N:15][N:14]2[C:10]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1c(CO)c(-c2ccccc2)c2c3ccccc3cnn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A stirred suspension of lithium aluminium hydride (1.0 g) in diethyl ether (40 ml) at 0° C. under an atmosphere of argon was treated with a solution of ethyl 3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine-2-carboxylate (2.35 g) in diethyl ether (60 ml). The reaction mixture was stirred at 0° C. for 2 hours and then it was quenched by dropwise treatment with ethyl acetate (50 ml). After stirring for a further period of 1 hour it was treated with saturated aqueous sodium sulphate solution (100 ml) and the resulting mixture was then extracted with ethyl acetate (3×100 ml). The combined extract was dried over magnesium sulphate and evaporated and the resulting residue was subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v), to give 2-hydroxymethyl-3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine (1.22 g) in the form of a yellow gummy solid. [NMR (in a mixture of CDCl3 and D2O): 1.57 (6H, d, J=7 Hz), 3.86 (1H, septet, J=7 Hz), 4.62 (2H, s), 7.25-7.53 (8H, m), 7.58-7.64 (1H, m), 8.3 (1H, s); Mass spectrum (electron impact) m/z=316].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].O>CS(C)=O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:25])[CH:19]([C:11]1[N:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)nn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (43.7 g) was added to a solution of 3,6-dichloropyridazine (10.0 g) and malonic acid diethyl ester (15.2 mL) in dimethyl sulfoxide (20 mL) at room temperature. The mixture was stirred at 110° C. for 1 h and then cooled to room temperature. Water and ethyl acetate were added and the resulting mixture was filtered over Celite. The aqueous phase of the filtrate was separated and extracted twice with ethyl acetate. The extracts and the organic phase of the filtrate were combined and washed with water and brine. Silica gel (50 g) and charcoal (5 g) were then added and the resulting mixture was stirred for 30 min at room temperature. The silica gel and charcoal were separated by filtration and the filtrate was concentrated to give the crude title compound that was used without further purification. Yield: 19.0 g (ca. 65% pure); LC (method 1): tR=1.25 min; Mass spectrum (ESI+): m/z=273/275 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[O:6])[CH2:2][CH3:3].CCCCCCCCC.CC(=[O:30])CCCCCCC>[Mn].[Cu]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([OH:30])=[O:6])[CH2:2][CH3:3]
Reactant: CCCCCCCC(C)=O
Reactant: CCCCCC(C=O)CCC
Agent: [Cu]
Agent: [Mn]
Solvent: CCCCCCCCC
Product: CCCCCC(CCC)C(=O)O

Procedure:
As shown in Table 3, the conversion of the 2-propylheptanal oxidation was considerably improved in the presence of a homogeneous copper-manganese catalyst compared to the uncatalysed reaction. The residue contents of 2-propyl-heptanal of about 10.42% by mass determined after 4 hours in the presence of catalyst are lower than the corresponding residue contents of 24.71% by mass of 2-propylheptanal in the uncatalysed oxidation. However, the selectivity of the catalysed oxidation was significantly worse compared to the oxidation without catalyst. As can be seen from Table 3, column 3, the selectivity in the homogeneously catalysed oxidation was reduced by the formation of by-products such as nonane and nonanone. As a result, the yield of isomeric decanecarboxylic acids is comparable to the yield in the uncatalysed oxidation despite higher conversions of about 55% by mass of 2-propylheptanoic acid.
Reaction SMILES: [OH:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][C:3]=1[O:17]C.[BrH:19]>>[BrH:19].[OH:17][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:2]=1[OH:1])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8]
Reactant: COc1cc(C[C@H](N)C(=O)O)cc([N+](=O)[O-])c1O
Agent: Br
Product: N[C@@H](Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)O

Procedure:
A solution containing 1.2 g of 4-hydroxy-3-methoxy-5-nitrophenylalanine hydrosulfate in 10 ml of conc. hydrobromic acid was refluxed for 2 h. The solution was concentrated in vacuo and allowed to stand over night in a refrigerator. The product was filtered and washed with hydrobromic acid and dried. Yield 0.25 g, m.p. 170° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][C:10]1[Te:11][C:12]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=2[N+:14]=1[CH3:15].[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22].C(OCC)C>C1C(O)=CC=CC=1C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:21]([O:23][CH:24]=[CH:9][C:10]1[Te:11][C:12]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=2[N+:14]=1[CH3:15])[CH3:22]
Reactant: Cc1ccc2[te]c(C)[n+](C)c2c1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CCOC=Cc1[te]c2ccc(C)cc2[n+]1C
Temperature: 140 °C

Procedure:
2,3,5-Trimethylbenzotellurazolium trifluoromethanesulfonate (Example 33) (0.84 g, 0.002 mole) was dissolved in m-cresol (1 ml). Triethoxymethane (0.89 g, 0.006 mole) was added, and the reaction mixture was heated in a 140° C. oil bath for five minutes. After cooling, diethyl ether (25 ml) was added with stirring. The solid was isolated by filtration, washed with diethyl ether, and dried at 40° C. under vacuum. Yield 0.85 g (89% of theory). The nuclear magnetic resonance spectra of the sample were in agreement with that expected for the structural formula.