Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CO>[C@H:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCc2ccccc21
Solvent: CO
Product: O[C@@H]1CCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl(R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.66 g (5.0 mmol) of 1-indanone and 4.4 ml of methanol were added thereto, then hydrogen gas was charged to 3.0 MPa. Subsequently, the mixture was stirred for 20 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-1-indanol was obtained at a conversion rate of 58.6% with an optical purity of 97.8% ee.
Reaction SMILES: [Na].[CH:2]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH2:15][C:16]#[N:17])=[CH:14][C:9]=3[N:8]([CH3:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3]1.[CH2:20]([OH:22])[CH3:21]>>[CH:2]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH:15]([C:20](=[O:22])[C:21]4[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=4)[C:16]#[N:17])=[CH:14][C:9]=3[N:8]([CH3:18])[C:7]2=[O:19])[CH2:3][CH2:4][CH2:5]1
Reactant: CCO
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CC#N)cc21
Agent: [Na]
Product: Cc1cccc(C(=O)C(C#N)c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Temperature: 75 °C

Procedure:
Sodium metal (1.2 g) was diluted with ethanol (12 mL). After dissolution (1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetonitrile (2.0 g, 8.29 mmol) was added followed by ethyl 3-methyl benzoate (2.0 mL). The reaction was heated to 75° C. for 2.5 hours then cooled and extracted into ethyl acetate from saturated sodium bicarbonate. Chromatography on silica gel gave the desired 2-(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=O)[C:5](=O)[C:4]=2[CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4]([CH:3]=1)=[C:5]1[C:6](=[C:7]3[CH:8]=[C:9]([Br:16])[CH:10]=[CH:11][C:12]=23)[N:22]=[CH:19][CH:20]=[N:21]1
Reactant: O=C1C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: NCCN
Solvent: CCO
Product: Brc1ccc2c3ccc(Br)cc3c3nccnc3c2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 2,7-dibromophenanthrene-9,10-dione (1.0 g, 2.7 mmol), ethylenediamine (1.8 mL, 26.9 mmol) and ethanol (20 mL) was heated to 85° C. After 3 hours, the reaction was cooled to room temperature and the solids were filtered and thoroughly washed methanol to yield 6,11-dibromodibenzo[f,h]quinoxaline (360 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[NH2:6].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C(O)(=O)C>[O:18]=[C:17]1[CH:16]=[CH:15][C:14](=[O:19])[N:6]1[C:5]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Temperature: 115 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 3-trifluoromethyl-4-cyano-aniline (24.0 g, 129 mmol) and maleic anhydride (14.0 g, 143 mmol) in 50 mL of acetic acid was heated at 115° C. overnight. A precipitate was obtained during the heating period. The reaction was allowed to stand at rt for an additional overnight period. The solid was removed by filtration, the filter cake was washed with diethyl ether and dried to give 21 g (79 mmol, 61%) of compound 471A as an off white solid. HPLC: 100% at 2.11 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15](O)=[O:16].C(Cl)(=O)C([Cl:22])=O>Cl>[CH3:1][C:2]1([CH3:18])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[C:15]([Cl:22])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(C(=O)O)=Nc2ccc3ccccc3c21
Agent: Cl
Product: CC1(C)C(C(=O)Cl)=Nc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg 1,1-dimethyl-1H-benzo[e]indole-2-carboxylic acid 3 (see under Example 1) were dissolved in 1.6 mL oxalyl chloride under vigorous developement of HCl-gas. While the solution was stirred at ambient temperature slowly a bright yellow began to precipitate. After 1.5 hours the reaction was complete and the excess of oxalylchloride was removed by distillation to give a yellow solid which was used without further purification.
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21]([OH:23])([CH3:4])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOCC
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 3.0 M solution of methylmagnesium bromide in Et2O (0.98 mL, 2.92 mmol), at 0° C., was added a solution of 3-oxoazetidine-1-carboxylic acid benzyl ester (0.5 g, 2.44 mmol) in anhydrous THF (5 mL) dropwise over 5 min under argon. The reaction mixture was stirred for 18 h at room temperature, and then quenched by addition of a saturated aqueous solution of NH4Cl (2.5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (10 mL) The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give 3-Hydroxy-3-methylazetidine-1-carboxylic acid benzyl ester as a colourless oil (0.54 g, 99%). LCMS (Method A): RT=3.60 min, [M+H]+ 221.9
Reaction SMILES: C([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])(=O)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+].[C:28](Cl)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]>O1CCOCC1.O>[C:28]([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCN(CCCC)C(C(=O)O)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(CCCC)C(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of compound (80) is dissolved in 30 mL of dioxane, and 10 mL of 6N hydrochloric acid solution is added, and the solution is refluxed overnight. The reaction is cooled to room temperature, concentrated to dryness, redissolved in 30 mL of tetrahydrofuran, and 10 mL of water and 30 mmol of sodium bicarbonate is added, followed by 15 mmol of Fmoc-Cl. The biphasic solution is stirred for 1 hour, and the tetrahydrofuran removed under vacuum. The aqueous solution is extracted with 1×50 mL of diethyl ether, acidified with 1N hydrochloric acid solution, and extracted with 2×50 mL of ethyl acetate. The ethyl acetate layers are combined, dry over sodium sulfate, and concentrated. Compound (81) is purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl[Sn]Cl.O.Cl>CCO>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH2:18]
Reactant: Cc1ccc(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(OCCCN2CCOCC2)cc1N

Procedure:
A solution of the 4-[3-(4-methyl-3-nitro-phenoxy)-propyl]-morpholine V-i (350 mg, 1.25 mmol) in 90% EtOH (15 mL) was treated with SnCl2.H2O (1.58 g, 6.24 mmol) and conc. HCl (1.04 mL, 12.5 mmol) and heated to reflux for 1 h. The cooled solution was concentrated under reduced pressure and taken to pH=8 with a saturated solution of NaHCO3 then extracted with EtOAc. The combined organics were dried (MgSO4), filtered and evaporated to the desired product V-g as a viscous yellow oil (306 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J=8.8 Hz, 1H), 6.30-6.24 (m, 2H), 3.96 (t, J=6.3 Hz, 2H), 3.76-3.69 (m, 4H), 3.58 (s, 2H), 2.57-2.42 (m, 6H), 2.09 (s, 3H), 1.93 (dt, J=13.3, 6.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(NC(=O)c2ccc3ccccc3c2)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CBr)cn1)c1ccc2ccccc2c1
Yield: 38.7 %

Procedure:
N-(5-methylpyridin-2-yl)-2-naphthamide (1.31 g, 5.0 mmol), N-bromosuccinimide (0.89 g, 5.0 mmol) and benzoyl peroxide (0.12 g, 0.5 mmol) were dissolved in carbon tetrachloride (50 mL), and reacted under protection of nitrogen for 16 hours. It was filtered while hot, and the filter cake was washed with carbon tetrachloride. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=5:1) to obtain a white solid 0.66 g, at a yield of 38.6%.
Reaction SMILES: C[Mg]Br.CCO[CH2:7][CH3:8].[Cl:9][C:10]1[N:15]=C(Cl)[N:13]=[C:12]([Cl:17])[N:11]=1.C(Cl)Cl.[O-][Mn](=O)(=O)=O.[K+]>>[Cl:9][C:10]1[N:11]=[C:12]([Cl:17])[N:13]=[C:7]([CH3:8])[N:15]=1
Reactant: CCOCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: C[Mg]Br
Agent: [K+]
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Methylmagnesium bromide, 3M in ether (Aldrich, St. Louis, Mo.) (10.0 mL, 30 mmol) was added slowly to a white suspension of 2,4,6-trichloro-1,3,5-triazine (Aldrich, St. Louis, Mo.) (3.68 g, 20 mmol) in DCM (25.0 mL, 389 mmol) at 0° C. and the resulting yellow suspension was warmed up to room temperature and stirring was continued until disappearance of starting material (TLC, KMnO4 stain, 3 h). The reaction was carefully quenched with NH4Cl(aq) at 0° C. and then diluted with water and DCM (25.0 mL). The separated organic layer was dried, filtered and concentrated to give 2,4-dichloro-6-methyl-1,3,5-triazine as a yellow solid (2.94 g, 90%) which was used for further reaction without purification. 1H-NMR (CDCl3, 400 MHz) δ 2.74 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)([OH:18])[C:9]([CH3:34])=[CH:8]2)[O:3]1.[CH:35]1(/[C:38](/I)=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1.[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.O1CCCC1>[CH:35]1(/[C:38](/[CH:20]=[CH:19]/[C:10]2([OH:18])[C:11]([CH3:17])([C:13]([F:16])([F:14])[F:15])[CH2:12][C:4]3([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]3)[CH:8]=[C:9]2[CH3:34])=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1
Reactant: CCOC(=O)/C=C(\I)C1CC1
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Under argon, 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (150 mg, 0.25 mmol) and ethyl (2Z)-3-cyclopropyl-3-iodoacrylate (67 mg, 0.25 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. tetrahydrofuran (4 ml), dichlorobis(acetonitrile)palladium(II) (3 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 36% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.80/7.78 (d, 1H), 6.40/6.38 (d, 1H), 5.62/5.60 (s, 1H), 5.52/5.44 (s, 1H), 4.28/3.63 (m, 2H), 4.18 (q, 2H), 2.52/2.41 (d, 1H), 2.03/1.94 (d, 1H), 2.00 (br. s, 1H, OH), 1.72/1.69 (s, 3H), 1.62/1.55 (m, 1H), 1.40-1.34 (m, 3H), 1.29-1.17 (m, 6H), 0.92 (t, 3H), 0.83 (m, 2H), 0.58 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37](OC1C=CC=CC=1)=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)Nc1ccccn1
Yield: 67.1 %

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(phenoxycarbonylamino)pentanoyl]oxyhexadecanamide (1.70 g) and 2-aminopyridine (2.56 g) in pyridine (10 ml) was stirred at 70° C. for 64 hours, and then poured into a mixture of ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml). The organic phase was washed with 1N hydrochloric acid (100 ml), 0.5N hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (50 ml) successively, dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on silica gel (300 cc) eluting with a mixture of dichloromethane and acetone (2:1 - 1:1) to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{3-(2-pyridyl)ureido}pentanoyl]oxyhexadecanamide (1.14 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Br[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:11])=[CH:8][CH:7]=1>CO>[CH3:1][O:2][CH:10]([Br:11])[C:9]1[CH:12]=[CH:13][CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium methylate, prepared from 11.8 g of sodium and 350 ml of methanol, is introduced dropwise into a suspension of 117.7 g of 4-bromobenzyl bromide in 350 ml of methanol. The mixture is stirred for 2 h at room temperature and left to stand overnight. The methanol is evaporated off, the residue is taken up in ether and the organic phase is washed with water and then dried and concentrated to give a yellow oil, which is purified by distillation to give 102 g of bromobenzyl methyl ether as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 51 %

Procedure:
3-Bromobenzaldehyde (18.5 g, 100 mmol) was added dropwise to a solution of potassium nitrate (20.2 g, 200 mmol) in concentrated sulfuric acid (100 mL) cooled to 0° C. by an ice water bath. The solution was stirred for an additional 15 minutes upon complete addition of 3-bromobenzaldehyde whereupon the entire reaction mixture was added to ice (250 g). The precipitate was isolated by filtration, and the solid was washed with de-ionized water until the pH of the wash was neutral. Drying for 12 hours under vacuum gave the yellow solid, 5-bromo-2-nitrobenzaldehyde was (11.8 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:20])[NH:7][C:6]=3[N:5]2[N:21]=1.[I:22]N1C(=O)CCC1=O>CN(C=O)C>[I:22][C:3]1[C:2]([CH3:1])=[N:21][N:5]2[C:6]3[C:11](=[CH:10][C:9]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([OH:20])[N:7]=3)[CH:12]=[N:13][C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Solvent: CN(C)C=O
Product: Cc1nn2c(ncc3cc(-c4ccccc4)c(O)nc32)c1I
Reaction time: 2 h

Procedure:
To a solution of Compound [IV] (0.2 g, 0.73 mmol, 1 eq.) in DMF (10 mL) was added N-iodosuccinimide (0.18 g, 0.8 mmol, 1.1 eq.) and the mixture stirred for 2 hours and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH (10%) as eluant to give Compound [XCVII]: LCMS ink 403 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.40 (m, 1H) 7.44 (t, J=7.42 Hz, 2H) 7.69 (d, J=7.22 Hz, 2H) 8.37 (s, 1H) 8.83 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27]([C:24]2[CH:23]=[C:22]([CH3:21])[O:26][N:25]=2)=[O:28])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cc(C(=O)O)no1
Agent: Cl
Product: Cc1cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)no1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 5-methylisoxazole-3-carboxylic acid. MS (m/e): 382.0 (MH−, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[S:27][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[C:9]3[CH:8]=[CH:7][S:27][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1cc2c(NCCc3ccc4c(c3)OCO4)ncnc2s1
Reactant: c1cn[nH]c1
Product: c1cnn(-c2nc(NCCc3ccc4c(c3)OCO4)c3ccsc3n2)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 6-chloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][CH2:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1.[ClH:30].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[ClH:30].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([N:28]3[CH2:27][CH2:26][NH:25][CH:24]([CH2:23][F:22])[CH2:29]3)=[O:20])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FCC1CNCCN1
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc2c(C(=O)N3CCNC(CF)C3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-indole-3-carboxylic acid (0.59 g, 2.04 mmol, prepared following the method in Example 1) and 2-(fluoromethyl) piperazine (0.37 g, 3.15 mmol) in dichloromethane (15 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 2.45 mmol) and 1-hydroxy benzotriazole (0.07 g, 0.51 mmol). The mixture was stirred at room temperature for 18 h and evaporated. The residue was purified by flash chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford the title compound (free base) as a colourless oil (0.47 g). The free base (0.05 g) was dissolved in diethyl ether (3 ml) and treated dropwise with 2 M hydrochloric acid in diethyl ether (1 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (10 ml) and dried under reduced pressure to afford the title compound (1:1 hydrochloric acid salt) as a colourless solid (0.05 g, 0.12 mmol). 1H NMR (400 MHz, CD3OD) δH 0.98-1.27 (5H, m), 1.57 (2H, br d, J 12.9), 1.63-1.90 (4H, m), 3.21-3.53 (4H, m), 3.68-3.79 (1H, m) 3.95 (3H, s), 4.26 (2H, d, J 7.1), 4.43-4.82 (4H, m), 6.77 (1H, d, J 7.7), 7.11 (1H, t, J 7.5), 7.27 (1H, d, J 8.0), 7.57 (1H, s); EIMS: m/z 270.2 [Fragment+H]+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][NH:18][N:17]=1.S(O[CH:44]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][N:18]([CH:48]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47]2)[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(C(=O)OC(C)(C)C)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a round bottom flask was added NaH (0.065 g, 1.6 mmol), DMF (4 mL) and 6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.500 g, 1.47 mmol, Example #L.1.1). The reaction mixture was stirred for about 30 min at ambient temperature. tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (0.652 g, 1.91 mmol, prepared according to US 2002/0151712, Example #34c) was added and the reaction mixture was stirred for about 30 min at ambient temperature. The reaction mixture was heated to about 75° C. for about 1 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 90:10) to give the title compound (0.446 g, 60%) as a mixture of regioisomers: LC/MS (Table 1, Method g) Rt=3.66 min; MS m/z: 510.4 (M+H)+.