Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:31]1([C:36]2C=C(CCC)C=[CH:40][CH:41]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:40][CH2:41][CH2:36][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[N:10]=[CH:9]1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCc1cccc(C2CCCC2)c1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(CCCOCCCC2CCCC2)c[nH]1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 3-cyclopentylphenylpropane chloride are treated as described in Example 5.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1([C:21]([O-:23])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1>CO>[CH3:1][O:22][C:21]([C:9]1([NH2:8])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)[O-])C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
Added (Trimethylsilyl)-diazomethane (2M in hexanes: 15 ml, 30 mmol) to a solution of 3-Amino pyrrolidine 1,3 dicarboxylic acid, 1-tert-butyl ester (900 mg, 3.9 mmol) in MeOH (5 ml) at room temperature. Stirred 10 minutes then evaporated solvent yielding 1T as an oil (0.9 g, 98%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH2:19][CH2:20][C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCC1CCCCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCC1CCCCC1)OC
Yield: 52.3 %

Procedure:
135 g. of dimethyl methylphosphonate were dissolved in 800 ml. of tetrahydrofuran, and to the solution cooled to -65°C., a solution of butyllithium [prepared from 163 g. of butyl bromide and 16 g. of lithium] in 610 ml. of diethyl ether was added drop-wise. To the reaction mixture was added drop-wise a solution of 62.5 g. of ethyl 3-cyclohexylpropionate in 300 ml. of tetrahydrofuran and the resulting mixture was stirred at the same temperature for two hours and afterwards at 0°C., overnight. The reaction mixture was then neutralised with acetic acid, concentrated under reduced pressure and after the addition of water extracted with diethyl ether. The ethereal extract was dried and the solvent distilled off. The residue was subjected to distillation under reduced pressure to obtain 51 g. (yield 52.3%) of the title product as a colourless oil, b.p. 143°-148°C./0.2 - 0.4 mm.Hg. NMR spectrum (tetrachloromethane): δ = 3.82 (6H, doublet), 3.16 (2H, doublet), 2.4 (2H, triplet), 1.97 - 1.08 (13H, multiplet).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][O:12][C:17](=[O:20])[CH2:18][CH3:19])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CC(=O)Cl
Product: CCC(=O)OC[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.
Reaction SMILES: OC[C:3]1[CH:8]=[C:7]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10])[CH:6]=[C:5](CO)[C:4]=1[OH:19].[C:20]1([CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[CH:22]=1)[OH:21].C1(C)C=CC=CC=1.Cl>O>[C:9]([C:7]1[CH:8]=[CH:3][C:4]([OH:19])=[CH:5][CH:6]=1)([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:11].[C:20]1([CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[CH:22]=1)[OH:21]
Reactant: CC(C)(C)CC(C)(C)c1cc(CO)c(O)c(CO)c1
Agent: Cl
Agent: Oc1cccc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Temperature: 80 °C

Procedure:
In a four-necked flask equipped with a fractionator and a thermometer were placed 66.5 g (0.25 mole) of 2,6-bis(hydroxymethyl)-4-t-octylphenol (purity: 99.1%) synthesized in the same manner as in the former half of Example 8, 82.5 g (0.75 mole) of resorcin and 100 ml of toluene, and 36% hydrochloric acid was added thereto so that the pH became 4, after which the temperature was elevated to 112° C. and then kept at that temperature for two hours while the water formed and toluene were removed by azeotropic distillation. The temperature was elevated to 150° C. and the reaction mixture was concentrated at a reduced pressure of 50 mmHg for one hour and then cooled to 80° C., after which 200 ml of toluene and 200 ml of water were added thereto to wash the mixture. The mixture was then allowed to stand to separate it into two layers. The upper layer (toluene solution) was transferred to a still, and then heated to 180° C., at which temperature the toluene solution was distilled at 3 mmHg for two hours to remove the toluene and unreacted resorcin, thereby obtaining a resorcin p-t-octylphenol resin [I].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([O:2][CH3:1])=[O:14]
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCCCCCCO
Temperature: 25 °C

Procedure:
To a solution of 165 mL (165 mmol) of a 1.0M solution of boranetetrahydrofuran complex in tetrahydrofuran in 200 mL of dry diethyl ether at 0° C. is added dropwise 25.0 g (123 mmol) of azelaic acid monomethyl ester, added at such a rate as to prevent excessive release of gas and exothermicity. The solution is allowed to warm to room temperature overnight and is worked up by slowly adding water until gas evolution ceases. Then solid potassium carbonate is added and the organic layer is separated. The aqueous layer is extracted three times with diethyl ether. The combined extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 8-carbomethoxyoctan-1-ol as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 146b (79 mg, 0.15 mmol), NaBH4 (22 mg, 0.60), and CH3OH (10 mL) was stirred at 25° C. for 1 h. The mixture was extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 146 (39 mg, 49%). LCMS: [M+H]+ 516. 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J=2.0, 1H), 8.78 (s, 1H), 8.52 (d, J=5.0, 1H), 8.35 (d, J=5.5, 1 H), 8.12 (s, 1H), 8.03 (d, J=2.0, 1H), 7.36 (d, J=5.0, 1H), 6.76-6.77 (m, 1H), 5.07 (s, 1H), 4.65 (d, J=9.5, 1H), 4.48 (d, J=9.5, 1H), 4.29 (d, J=1.5, 1H), 4.02-4.13 (m, 2H), 3.79 (d, J=6.5, 1H), 3.73 (s, 3H), 2.52-2.58 (m, 4H), 1.85-1.90 (m, 2H), 1.77 (d, J=5.0, 2 H)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH2:35][CH3:36])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:37][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C:11]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:37])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=1)[CH3:36]
Reactant: [Li]C
Reactant: CCCc1nc(CC)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.63 g) in tetrahydrofuran (10 mL) was added methyllithium (1.2 mL, 2.2 M diethyl ether solution) under ice-cooling, and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.54 g, 83%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]12[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10]C(=O)O[C:6]2=[O:7]>C1COCC1.CCN(C(C)C)C(C)C>[NH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=1[C:6]([NH:4][O:3][CH3:2])=[O:7]
Reactant: CON
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccccc1N
Reaction time: 3 h
Yield: 49.5 %

Procedure:
O-methylhydroxylamine hydrochloride (1.79 g) was added to isatoic anhydride (2.34 g) in THF (72 mL) and DIPEA (4 mL). The reaction was stirred for 3 hours and then heated to reflux overnight. The reaction was then cooled and concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL), the aqueous phase basified with potassium carbonate (˜15 g) and the organics discarded. The aqueous was then extracted with EtOAc (3×75 mL). The combined organics were dried (MgSO4, 20 g) and concentrated. The product was dried overnight at 40° C. under vacuum to give 2-amino-N-methoxybenzamide (1.18 g, 50% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:38])=[C:19]([C:21]4[NH:25][C:24]([CH:26]5[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)=[N:23][C:22]=4[CH3:37])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[NH:28]1[CH2:29][CH:26]([C:24]2[NH:25][C:21]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][C:18]=3[CH3:38])[C:13]([N:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH2:12]3)=[O:14])=[C:22]([CH3:37])[N:23]=2)[CH2:27]1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CN(C(=O)OC(C)(C)C)C2)nc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CNC2)nc1C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 3-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate (compound 189.1, 2 g, 3.91 mmol) in 1,4-dioxane (20 mL). Hydrogen chloride (4 M) (10 mL) was added to the reaction. The reaction mixture was stirred for 2 h at 30° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 7-8 with sodium bicarbonate (sat.). The resulting mixture was concentrated under reduced pressure to give 800 mg (crude) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:26]=4)[N:23]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:35]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:26]=4)[N:23]=3)[CH2:12][CH2:13]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 84.5 %

Procedure:
482 mg of ethyl 2-[6-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 2 ml of ethanol; 1.8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 1 hour. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5 by the addition of 1 N hydrochloric acid. Ethyl acetate was added to cause crystallization; the crystal precipitated was washed with water-acetone (2:1) and dried to yield 386 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23]CC)=[O:22])=[O:15])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([OH:23])=[O:22])=[O:15])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NCC(=O)C=Cc2cc(C(C)C)c(C(C)C)o2)c1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1cc(C=CC(=O)CNc2cccc(C(=O)O)c2)oc1C(C)C
Yield: 94.2 %

Procedure:
This ester (94 mg, 0.245 mmol) was hydrolyzed with lithium hydroxide in a conventional manner, and the residue was recrystallized to obtain the title compound (29, 82 mg, 94%) as colorless prisms.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[C:17]#[C:18][C:19]2[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[CH:6][C:5]=1[Cl:26].[OH-].[Na+]>C1COCC1>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([C:18]#[C:17][C:11]2[C:12]([CH3:16])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([Cl:26])[CH:6]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(-c2ccnc(C)c2C#Cc2ccc(N)nc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 460 mg (1.2 mmol) 4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-chloro-benzoic acid methyl ester using 2.4 mL (2.4 mmoL) 1 N NaOH in 10 mL THF. The product is purified by chromatography on silica gel using an DCM/MeOH-gradient (100:0 to 90:10, NH3). Yield: 420 mg (95%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>C(OCC)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([CH2:13][CH:12]=[CH2:11])[OH:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under anhydrous condition at 0° C., a minute of 18.0 g of freshly distilled 2,4-difluorobenzaldehyde and 120 ml of diethyl ether is treated, dropwise, with 139 ml of 1M allyl magnesium bromide. The reaction is stirred at 0° C. for 1 hour then slowly allowed to warm to room temperature. After 5 hours, thin layer chromatography indicates complete reaction. The mixture is cooled to 0° C. and quenched by the dropwise addition of 100 ml of ice cold saturated ammonium chloride. Two hundred ml of diethyl ether is added and the layers are separated. The aqueous layer is extracted with diethyl ether. The organic layers are combined, washed twice with saturated sodium chloride, dried , filtered and concentrated in vacuo. The residue is purified by Kugelrohr distillation (100° C.) to give 19.9 g of the desired product as a mixture of isomers.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(OCCOCCO)C.CO.C[O-].[Na+]>O.COCCOCCOC.CCCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=2[CH3:26])=[O:16])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOCCOCCO
Solvent: COCCOCCOC
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 91.3 %

Procedure:
In a 10 L-reaction flask equipped with a rectification column and a separating tank, 314 g (1.81 mol) of 4-tert-butylphenylacetonitrile, 300 g (1.65 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 3000 g of heptane, 225 g of diethylene glycol dimethyl ether, and 99 g of diethylene glycol monoethyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 381 g (1.98 mol) of 28% sodium methoxide methanol solution was added dropwise over 10 hours, and the resulting mixture was further reacted for 7 hours. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was further washed with 600 g of heptane to separate out heptane phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 466 g (yield 91.5%) of 2-(4-tert-butylphenyl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. After adding 2760 g of xylene to the aqueous phase, 206 g (1.98 mol) of 35% hydrochloric acid was added dropwise to be neutralized. After separating out the aqueous phase, the resulting organic phase was washed two times with 600 g of water and the aqueous phase was separated out to obtain xylene solution of 3-oxo-2(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile. A quantitative analysis with liquid chromatography showed that the xylene solution contained 456 g (yield 89.6%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(O)(=O)C>N>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Reactant: Nc1ccc(F)cc1F
Agent: N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Temperature: 75 °C
Yield: 87.9 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 4-chloro-6,7-dimethoxycinnoline-3-carboxylate (0.200 g, 0.675 mmol) (Method 7) was added anhydrous ethanol (10 mL), 2,4-difluoroaniline (0.087 g, 0.675 mmol), and glacial acetic acid (˜100 μL). The reaction mixture was then heated to 75° C. for 1 h, cooled to rt, and diluted with concentrated aqueous ammonia (˜5 mL). The crude product precipitated from this reaction mixture and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield the crude product which was purified on 40 g silica using EtOAc as eluent providing 0.231 g (88%) of the title compound as a yellow solid. 1H NMR: 9.25 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.02 (s, 3H), 3.95 (q, 2H), 3.85 (s, 3H), 1.20 (t, 3H); m/z 390.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:4]([CH3:27])[N:3]=1.Cl>CCO>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([NH2:1])=[N:3][N:4]4[CH3:27])=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4C(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CCO
Product: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4)cccc21
Temperature: 75 °C
Yield: 91.7 %

Procedure:
To a stirred suspension of 1,1-dimethylethyl 5-(3-amino-1-methyl-1H-indazol-4-yl)-2,3-dihydro-1H-indole-1-carboxylate (1.70 g, 4.66 mmol) in 20 mL of EtOH was added 12 mL of 2N HCl. The mixture was heated at 75° C. for 90 min. LCMS showed conversion complete. The mixture was cooled, and concentrated in vacuo. The oily residue was diluted with 40 mL of water, and the pH was adjusted to ˜10 by adding 1N NaOH (pH paper). The milky mixture was extracted with 10° A MeOH in DCM (100 mL, then 2×25 mL). The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-indazol-3-amine as a brownish foamy solid (1.13 g). LC-MS (ES) m/z=265 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[CH:23](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[C:18]([F:21])=[C:19]([F:20])[C:2]4[N:1]=[CH:23][O:22][C:3]=4[C:4]=3[NH:8][C:7]2=[O:9])=[C:11]([F:17])[CH:12]=1
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(Br)cc2F)c1O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(Br)cc1F
Yield: 65 %

Procedure:
Intermediate I-16a was prepared from 5-amino-1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-14a: 800 mg, 2.14 mmol), triethyl orthoformate (3.7 mL) and p-toluene sulfonic acid (80 mg) using procedures analogous to those used to prepare Intermediate I-15a above to afford 550 mg of the product (65% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.50 (s, 1H), 8.80 (s 1H), 7.97 (d, 1H), 7.65-7.55 (m, 2H). HPLC: 95.7%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[CH:23]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:23]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2=NCc3nncn3-c3ccc(Cl)cc32)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.6 parts of 7-chloro-2-hydrazino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine in 50 parts by volume of ethanol is added 3 parts of ethyl orthoformate. To the mixture is added 0.5 part by volume of concentrated sulfuric acid with stirring. After 5 minutes, the reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution, followed by removal of the solvent. To the residue is added water, whereupon 8-chloro-6-(4-methoxyphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is obtained as crystals. Recrystallization from acetone-ethyl acetate gives pale yellow flakes melting at 216°-217° C.