Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]1[O:17][CH:18]=[C:19]([C:21](OC)=[O:22])[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].C(OCC)(=O)C.Cl>C1COCC1.O>[OH:22][CH2:21][C:19]1[N:20]=[C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[O:17][CH:18]=1
Reactant: COC(=O)c1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1c1nc(CO)co1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of (R)-methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4-carboxylate (6.95 g, 21.1 mmoles) in THF (50 mL) at 0° C., was added LiBH4 (32 mL, 2.0M in THF, 63.2 mmoles). The reaction was allowed to warm to room temperature and stirred for 3 h. Ethyl acetate (25 mL) was added drop-wise and stirred for 30 min. The reaction was cooled to 0° C. and 50 mL of 1N HCl was added drop-wise and diluted with 100 mL of water. It was then extracted with ethyl acetate, dried on Na2SO4, concentrated, and chromatographed on silica gel (3% MeOH/97% chloroform) to yield 4.1 g of (R)-benzyl 2-(4-(hydroxymethyl)oxazol-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:13]([OH:23])[CH:14]([NH2:22])CC1C=CC=CC=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1.O>C(O)C.ClCCl>[C:1]([NH:11][C@@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@H:13]([OH:23])[CH2:14][N:22]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:34](=[O:35])[CH2:33][C:32](=[O:36])[CH3:31])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C=C1CC(=O)O1
Reactant: NC(Cc1ccccc1)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(=O)CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
The Cbz protected amino alcohol (IX) (0.080 g, 0.19 mmol) was dissolved in 2 ml of ethanol and to this diketene (23 μL, 0.29 mmol) was added dropwise. The reaction mixture was then stirred for 1 hour and diluted with 4 ml dichloromethane. It was then poured into water and the organic layer was separated, and dried (Na2SO4). It was then subjected to silica gel chromatography with 2:1 hexane/ethyl acetate as an eluent to give the keto-amide (XI) as oil. 100 mg (98% yield) 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.52-4.87 (m, 2H), 3.75-4.00 (m, 2H), 3.28-3.51 (m, 1H), 2.75-2.94 (m, 2H), 2.43 (s, 2H), 2.05 (s, 3H). 13CNMR (125 MHz, CDCl3) 201.2, 168.4, 155.85, 140.91, 140.36, 138.22, 129.15, 128.68, 128.56, 128.37, 128.10, 127.72, 127.41, 127.64, 126.75, 80.23, 60.18, 54.14, 50.15, 7.99, 43.6, 37.43, 25.7.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:16]([CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)(=O)[CH3:17].[O-]CC.[Na+]>C(O)C.O>[CH3:17][C:16]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=12
Reactant: CC(=O)C1CCCC1=O
Reactant: CCOC(=O)CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1[nH]c(C)c2c1CCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A procedure for the synthesis of pyrroles via N-(3-oxo-1-alkenyl)glycine ester was adapted from Hombrecher and Horter, Synthesis 389, 1990. Ethyl aminoacetate hydrochloride (28 g, 0.20 mol) and triethylamine (20.1 g, 0.20 mol) were added to a solution of 2-acetylcyclopentanone (25.0 g, 0.20mol) in ethanol (400 ml). The solution was stirred at room temperature for 15 hours and concentrated. The residue was combined with water (250 ml), and extracted with methylene chloride (4×100 ml). The combined extract was washed with water (100 ml), dried (sodium sulfate), and concentrated to leave a light brown oil. The oil was added with stirring at 50° C. to a solution of sodium ethoxide (14 g, 0.20 mol) in absolute ethanol (400 ml). The mixture was heated at 80° C. for 3 hours and poured into water (500 ml) to precipitate a light yellow solid. Recrystallization from ethanol gave ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j, 9.1 g (24%)as a pale yellow solid, mp 166°-167° C.; 1H NMR (CDCl3): δ 8.38 (s, 1H), 4.24 (q, 2H), 2.78 (t, 2H), 2.52 (t, 2H), 2.30 (m, 2H), 2.18 (s, 3H), 1.30 (t, 3H). Anal. calcd for C11H15NO2 : C, 68.39; H, 7.77; N, 7.25. Found, C, 68.40; H, 7.85; N, 7.15.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH2:5]1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH2:5]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C(N)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCC[C@H](C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
In a 25 mL pear-shaped flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-carbamoyl-cyclohexyl)-amide (72 mg, 0.124 mmol) was combined with pyridine (412 μl) to give a off-white solution. The reaction mixture was cooled at 0° C. and trifluoroacetic anhydride (0.71 M in pyridine, 26 μl, 0.18 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 30 min and then concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 27 mg (39%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-cyano-cyclohexyl)-amide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.14 (s, 1H), 8.66 (s, 1H), 8.40 (d, J=8.7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 8.01 (d, J=1.0 Hz, 1H), 7.38 (dd, J=8.7, 1.0 Hz, 1H), 5.73 (s, 2H), 4.18 (s, 3H), 4.09-4.28 (m, 1H), 3.59 (t, J=7.9 Hz, 2H), 3.41-3.60 (br. s., 1H), 2.24 (app. d, J=12.5 Hz, 1H), 2.07 (app. d, J=12.1 Hz, 1H), 1.59-1.91 (m, 5H), 1.39-1.59 (m, 1H), 0.86 (t, J=7.9 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [C:1](=[O:4])([OH:3])N.[NH:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]>C1C=CC=CC=1>[C:1](=[O:4])=[O:3].[NH:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]
Reactant: NC(=O)O
Solvent: c1ccccc1
Solvent: OCCNCCO
Product: O=C=O

Procedure:
In this example, it was asserted that a white, pulverulent diethanolamine carbamate was obtained by the introduction of carbon dioxide into a solution of diethanolamine in benzene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine (1 mole) was treated with ethyl chloroformate (1.1 mole) in pyridine to give 3-chloro-6-(4-ethoxycarbonyloxy-2-hydroxyphenyl)pyridazine.
Reaction SMILES: [Na].C1(S(N)(=O)=O)C=CC=CC=1.C1([N:18](C2C=CC=CC=2)[C:19]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([Cl:28])[CH2:24][CH2:23]2)=[O:20])C=CC=CC=1.CN(C)C=O.N>O>[Cl:28][CH:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:19](=[O:20])[NH2:18])[CH2:27][CH2:26]1
Reactant: O=C(NC1CCC(Cl)CC1)N(c1ccccc1)c1ccccc1
Agent: N
Agent: NS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)NC1CCC(Cl)CC1

Procedure:
3.9 g of 4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonamide sodium, 6.5 g of N.N-diphenyl-N'-(4-chlorocyclohexyl)-urea (melting point 115° -116°C) and 100 ml dimethyl formamide are heated to 110°C for 45 minutes. Then the whole is cooled, poured into water and ammonia of 1 % strength is added. Then the whole is filtered, the filtrate is acidified and the precipitate obtained is purified once more over ammonia/hydrochloric acid. The N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4-chlorocyclohexyl)-urea precipitating in crystalline form melts at 178° -179°C after recrystallization from methanol/dimethylformamide.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[F:25][C:26]([F:36])([F:35])C1C=CC=C(NN)C=1>C(N(CC)CC)C>[F:25][C:26]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)[CH:19]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(C(F)(F)F)c1

Procedure:
A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.7 grams α,α,α-trifluoro-3-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 grams 1,4-bis-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 207°-208° C. A 1.8 gram portion of the above pyrazolinone was alkylated with 2 grams methyl iodide to produce 1.25 grams of the desired product, m.p. 110°-111° C.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Si:13]([O:20][CH:21]([C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=1)[C:22]([O:24][CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C([SiH](CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Si:13]([O:20][CH:21]([C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=1)[CH2:22][O:24][CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.27 mmol of titanium tetrachloride in 1.5 ml of dichloromethane is added to a solution of 2.61 mmol of trimethylsilyl trifluoromethanesulphonate in 1 ml of dichloromethane at 0° C. The mixture is stirred at room temperature for 4 hours and then cooled to 0° C. A solution of 0.83 mmol of 1-trityl-1H-imidazol-4-ylmethyl (tert-butyldimethylsilyloxy)(4-cyanophenyl)acetate and 4.17 mmol of triethylsilane in 2 ml of dichloromethane is added, and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.CC[O:13][C:14]([CH:16]([C:20]([CH3:22])=O)[C:17]([CH3:19])=O)=[O:15]>C(O)(=O)C>[C:7]([C:5]1[CH:6]=[C:2]2[N:1]=[C:17]([CH3:19])[C:16]([C:14]([OH:15])=[O:13])=[C:20]([CH3:22])[N:3]2[N:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2cc(C(C)(C)C)nn2c(C)c1C(=O)O
Temperature: 120 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
3-Amino-5-t-butylpyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred for 3 hours at 120° C. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N sodium hydroxide solution (3 ml) were added to the residue and then stirred for 1 hour at 70° C. The mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (2.1 g, Y.:78%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]#[C:11][CH:12]([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C[N:16](C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]2[N:4]([N:16]=[C:11]([CH:12]([CH3:14])[CH3:13])[CH:10]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(C#CC(C)C)n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(C(C)C)nn12
Reaction time: 4 h

Procedure:
The compound of Example 261 (28.9 g) was added to a solution of MSH (26.1 g) in methylene chloride (250 mL) and the mixture was stirred for 4 hours, followed by concentration of the solvent and sequential addition of DMF (250 mL) and potassium carbonate (65.1 g). The resulting mixture was vigorously stirred at room temperature for 2 hours. Subsequently, saturated brine was added and the mixture was extracted with ether. The organic layer was dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (10 to 30% methylene chloride/petroleum ether). The purified product was solidified in petroleum ether to afford the title compound as a colorless powder (5.14 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH2:24][C:25]#[N:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:24][C:25]#[N:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC#N)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-t-butyldimethylsilyloxypyrrolidine (88 g) in methanol (450 ml), 6N hydrochloric acid (45 ml) was added, and the resultant mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-hydroxypyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[NH:14][C:13]2[CH:15]=[CH:16][N:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:12]=2[C:11](=[O:23])[N:10]1[C@H:24]([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]([C@H:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11](=[O:23])[C:12]2[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1C1Nc2ccnc(C(F)(F)F)c2C(=O)N1[C@H](C)Cc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1[C@H](C)Cc1ccccc1

Procedure:
2-(2-methoxyphenyl)-3-((R)-1-phenylpropan-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (19.04 g, 43.13 mmol) was dissolved in acetone (800 mL). To this was added a 5% aqueous solution of potassium permanganate (34.1 g KMnO4 in 700 mL water). The resultant mixture was stirred at room temperature overnight. The reaction was quenched by pouring it into a 10% aqueous solution of sodium bisulfite (3 L). The resulting aqueous solution was extracted with ethyl acetate (3×700 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide an oil. This oil was purified by flash chromatography using 25-50% ethyl acetate/heptanes as eluant to provide the product as a solid. This solid was recrystallized from ethyl acetate/hexanes to yield a colorless solid (12.5 g). 1H NMR (400 MHz, CDCl3) δ 8.8 (d, 1H), 7.65 (d, 1H), 7.4 (t, 1H), 7.15 (m, 7H), 6.95 (t, 1H), 6.8 (d, 1H), 6.35 (d, 1H), 4.2 (m, 1H), 3.8 (s, 3H), 3.6 (dd, 1H), 2.9 (dd, 1H), 1.75 (d, 3H). MS m/z 440.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[N:32]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccc(F)cc2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccc(F)cc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 6-(4-fluorophenyl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 421.35 g/mol.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1>>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCc1ccco1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCc1ccco1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-(aminomethyl)furan.
Reaction SMILES: [N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][N:35]([Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[C:32]3=[N:33][CH:34]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:29]4[CH:30]=[C:31]5[CH:37]=[CH:36][N:35]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:39]([CH3:40])[CH3:41])[C:32]5=[N:33][CH:34]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Ic1ccc2ncnc(N3CCc4ccccc43)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCc6ccccc65)c4c3)cnc21
Yield: 73.4 %

Procedure:
0.20 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline, 0.21 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 0.13 g of sodium hydrogencarbonate and 0.07 g of Pd(PPh3)2Cl2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 5 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography; (gradient heptane: EA 5-100% in 16 min), giving 0.20 g of 4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline as white powder (yield 71%, content 99%); EI-MS (M+H+)=519.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of methyl 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoate (645 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (589 mg, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][N:46]3[C:49]([C:52](OCC)=[O:53])=[CH:50][N:51]=[C:45]3[CH:44]=2)[CH2:36][CH2:35]1>C1COCC1>[CH3:18][N:17]([CH3:19])[C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:52]([C:49]3[N:46]4[CH:47]=[CH:48][C:43]([O:42][CH2:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:44][C:45]4=[N:51][CH:50]=3)=[O:53])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1)=[O:16]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: CN(C)C(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4cccc(C(=O)N(C)C)c4)cnc3c2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 3-((4-amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.15 g, 0.51 mmol) and THF (1.0 mL) was cooled to −5° C. in an ice/brine bath, then LHMDS (0.48 ml, 0.48 mmol, 1.0M THF) was added drop-wise and the mixture was stirred for 10 minutes, during which a dark emulsion formed. Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.080 g, 0.24 mmol) was added dropwise as a THF solution (1.0 mL). The reaction was stirred at −5 to 0° C. for 1 hour, then quenched with saturated aqueous NH4Cl (10 mL). The mixture was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was slurried in Et2O with vigorous stirring and then filtered through a nylon filter providing crude product with >90% purity (0.083 g). The crude product was purified by column chromatography (5 to 20% MeOH/CH2Cl2 using 5% NH4OH/MeOH). The fractions were concentrated and the product dissolved in CH2Cl2 and then filtered. The filtrate was concentrated to provide N-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a pale orange solid (0.060 g). This product was dissolved in MeOH (2.4 mL) and then HCl (2.41 mL, 4.81 mmol, 2.0M Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and hexanes and dried under vacuum to provide 0.050 g (31%) of the title product as a pale brown powder. MS (ES+APCI) m/z=581 (M+H-2HCl).