Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[OH:3][C:4]1[C:11]([I:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:13][CH3:14])[N:5]=1>O1CCOCC1.C(=O)([O-])[O-].[Ag+2]>[I:12][C:11]1[C:4]([O:3][CH3:1])=[N:5][C:6]([S:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CI
Reactant: CSc1nc(O)c(I)cc1C#N
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1nc(SC)c(C#N)cc1I
Temperature: 60 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
905 μl (2 eq) of methyl iodide and 2.1 g (1.05 eq) of silver carbonate are added successively to a solution of 2.12 g (7.26 mmol) of 6-hydroxy-5-iodo-2-(methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is stirred at 60° C. for 5 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and the residue purified by silica column chromatography (4:6 dichloromethane/cyclohexane as eluent) to yield 1.52 g (68%) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[NH4+].[Cl-]>CS(C)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]#[N:12]
Reactant: Brc1ccccn1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(C(C#N)c2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add dropwise over a 1-hour period a mixed solution of 2-(2,4,6-trimethylphenyl)ethanenitrile (20 g; 0.126 mol) and 2-bromopyridine (35 g; 0.22 mol) in DMSO (25 mL) to a solution of potassium t-butoxide (35 g; 0.31 mol) dissolved in DMSO (125 mL). After the addition, stir the mixture for 4 h at ambient temperature and slowly pour into a stirred, ice-cold solution of NH4Cl with vigorous stirring. Filter the resulting tan precipitate, wash with MeOH, and air-dry to obtain the title compound as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 6H), 2.32 (s, 3H), 5.76 (s, 1H), 6.93 (s, 2H), 7.12 (d, 1H), 7.21 (dd, 1H), 7.63 (t, 1H), 8.63 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1
Reactant: COC(=O)c1sc(C)nc1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
5.00 g (18.6 mmol) of methyl 4-(2-chlorophenyl)-2-methyl-1,3-thiazole-5-carboxylate and 3.38 g (19.0 mmol) of N-bromosuccinimide were dissolved in 100 ml of carbon tetrachloride and, with stirring, heated to the boil. At boiling point, 170 mg (1.00 mmol) of 2,2′-azobis-2-methylpropionitrile were added a little at a time over a period of 5 hours, followed by refluxing for a further hour. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The desired product was isolated by chromatographic purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[N:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:30].C[O:34][C:35]1[CH2:40][CH2:39][CH2:38][C:37](=O)[CH:36]=1.Cl>CCCCCC.C1COCC1.C(Cl)(Cl)Cl>[O:34]=[C:35]1[CH2:40][CH2:39][CH2:38][C:37]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][NH:23][C:24]2=[O:30])=[CH:36]1
Reactant: COC1=CC(=O)CCC1
Reactant: C[Si](C)(C)N1CCCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C1C=C(C2CCCCNC2=O)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
Lithium diisopropylamide, prepared by treating diisopropylamine (45.3 ml) with 1.4 M butyl lithium in hexane (231 ml) at -10° C. under nitrogen, was treated at -60° C. with 1-trimethylsilylhexahydro-2H-azepin-2-one (63.7 g) in dry THF (50 ml). The white suspension was treated after 20 minutes with a solution of 3-methoxy-2-cyclohexenone (40.8 g) in THF (50 ml). The resulting solution was allowed to warm to ambient temperature. After a further 3 hours the cooled solution was treated with concentrated hydrochloric acid (120 ml) and stirred for 18 hours. The THF layer was combined with several chloroform extracts from the aqueous layer. Evaporation of the solvent gave a yellow solid, which was recrystallised from ethyl acetate to give hexahydro 3-(3-oxocyclohexen-1-yl) -2H-azepin-2-one as an off-white solid (45.5 g) m.p. 159°-165° C.
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:42]=[O:43])C>C1COCC1.C1CCCCC1>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:8]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([F:13])=[C:11]([CH:12]=1)[CH:42]=[O:43])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)c(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: -78 °C

Procedure:
A solution of 55.0 g of 4-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxy)-fluorobenzene described in example 3.1 in 120 ml THF was cooled to −78° C. Within 30 min 97 ml of an 1.3 M solution of sec-butyllithium in cyclohexane was added dropwise. After stirring at −78° C. for an hour, 9.7 DMF in 18.3 ml THF was added within 20 min. The mixture was stirred at −78° C. for 1 hr, then warmed to r.t. within 90 min and quenched with 300 ml ice-cold water. The product was isolated by extraction with Et2O to yield 60.6 g 5-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-benzaldehyde as yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])(=[O:12])[CH3:11]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1Cl

Procedure:
Preparation according to Preparation 16 using 4-bromo-2-chlorophenol (6 g, 29 mmol) and acetic anhydride (13.4 g, 130 mmol) in pyridine (10.5 ml, 130 mmol). Yield 7.4 g. MS m/z (rel. intensity, 70 eV) 210 (25), 208 (bp), 206 (79), 63 (21), 62 (9), 250 (M+, 8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:10]([CH3:19])[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccccc1)n1cc(Cl)cnc1=O

Procedure:
A solution of 5-chloropyrimidin-2-one (394 mg) and α-bromopropiophenone (0.5 ml) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2.75 hours. The solution was evaporated and the residue was triturated with water (50 ml) giving an oily solid. This was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and evaporated to a gum. This was crystallised from acetone-petrol (b.p. 40°-60°) to give the title pyrimidinone (306 mg,); m.p. 125°-127°; λmaxEtOH 232 nm (ε 15400), 245 nm (ε 15480), 335 nm (ε 3970).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([CH2:23][NH:24]C(=O)C(F)(F)F)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[NH2:24][CH2:23][C:10]1([N:7]2[CH2:8][CH2:9][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH2:6]2)[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)(N2CCN(C3CC3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(N2CCN(C3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of tert-butyl 4-(4-cyclopropylpiperazin-1-yl)-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (3.22 mmol) in methanol (8 ml) was added 1 N NaOH solution (13 ml) and the reaction mixture was stirred at room temperature for 2 h. After completion the reaction mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to obtain the desired product. Yield: 90%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:21].CCCCOCCO>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCOCCO
Product: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12

Procedure:
A 14.0 g amount of 4-amino-1,5-naphthalenedisulfonic acid is suspended in 100 ml of water and the solution is made basic with 5 N sodium hydroxide. The solution is warmed and absolute ether alcohol is added until a solid is precipitated. The solid is collected by filtration and is washed with 85% aqueous ethyl alcohol, ethyl alcohol and ether, then dried in vacuo to yield 12.0 g of 4-amino-1,5-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C(O)C.[Ni]>[NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: Nc1cnc2ccccc2c1
Agent: [Ni]
Solvent: CCO
Product: NC1CNc2ccccc2C1

Procedure:
The solution of 35 g of 3-aminoquinoline in 330 ml of ethanol is hydrogenated in the presence of a total of 27 g of Raney nickel at 55° C. under a pressure of 90 bar for 44 h. After customary working up, the crude product is purified over 900 g of silica gel (mobile phase S): Rf (S)=0.40; MS: M+ =148.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH2:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29](OC=O)(=[O:31])C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:19])[CH3:20])=[C:13]([NH:21][CH:29]=[O:31])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester (0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) in CH2Cl2 (7.5 mL) was cooled to 0° C., and a solution of formic-acetic anhydride (3.5 mmol, prepared by mixing formic acid (158 μL, 4.2 mmol, 1.3 equiv) and acetic anhydride (0.32 mL, 3.5 mmol, 1.1 eq.) neat and ageing for 1 hour) in CH2Cl2 (2.5 mL) was added dropwise over 2 min. After the addition was complete, the mixture was allowed to warm to room temperature, whereupon it deposited a precipitate, and the resulting slurry was stirred overnight. The mixture was washed with 1 M citric acid (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), and filtered. The cloudy mixture deposited a thin bed of solid above the drying agent, HPLC analysis showed this to be the desired formamide. The filtrate was concentrated to approximately 5 mL, and diluted with hexane (15 mL) to precipitate further formamide. The drying agent (Na2SO4) was slurried with methanol (50 mL), filtered, and the filtrate combined with material from the CH2Cl2/hexane recrystallisation. The resultant mixture was concentrated to afford (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester as an off-white solid (650 mg, 50% over 2 steps). 1H and 13C NMR (CD3OD) show the product as a rotameric mixture. 1H NMR (400 MHz, CD3OD, rotameric) δ 8.27 (s, 1H-a), 8.17 (s, 1H-b), 7.42-7.26 (m, 8H), 5.17 (s, 1H-a), 5.15 (s, 1H-b), 4.86 (s, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H-b); 13C NMR (100 MHz, CD3OD, rotameric) δ 1636.9, 163.5, 155.8, 141.40, 141.32, 139.37, 138.88, 138.22, 138.14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24, 129.19, 129.13, 128.94, 128.50, 121.4 (br), 118.7 (br), 67.80, 67.67, 35.78, 35.52, 31.65, 31.34; ESI-MS 327.5 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.Cl[C:19]1[N:24]=[N:23][C:22]([C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:19]3[N:24]=[N:23][C:22]([C:25]4[S:29][N:28]=[C:27]([CH3:30])[N:26]=4)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Agent: Cl
Product: Cc1nsc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)n1

Procedure:
5-(6-(4-(6-Fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-3-methyl-1,2,4-thiadiazole was prepared according to the procedure as described in Example 1, Method B, STEP 2, reacting 6-fluoro-1-(piperidin-4-yl)indoline as its corresponding HCl salt and 5-(6-chloropyridazin-3-yl)-3-methyl-1,2,4-thiadiazole, prepared as in STEP 1 above.
Reaction SMILES: Br[C:2]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(CC(=O)C)(=O)C.[Ni].C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]([C:5]2[N:10]3[N:11]=[CH:12][N:13]=[C:9]3[N:8]=[CH:7][CH:6]=2)([CH3:4])[CH3:3])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(Br)c1ccnc2ncnn12
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CC(C)(Oc1ccc(Cl)cc1)c1ccnc2ncnn12

Procedure:
A mixture of 7-(1-bromo-1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.95 g, prepared in a similar manner to that described above), 4-chlorophenol (1.56 g), sodium bicarbonate (1 g), nickel acetyl acetone (5 mg) and dry toluene (80 ml) was stirred and heated under reflux for 7 days. The solvent was evaporated and the crude product was purified by flash chromatography using as eluent a mixture of toluene and ethylacetate (in the ratio 5:1 respectively), followed by recrystallisation from n-hexane, to give 7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.67 g, (mp 132°-135° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:20])([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH2:23][CH2:22]1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH:20][C:29](=[O:30])/[CH:28]=[CH:27]/[CH:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)([O-:3])=[O:2]
Reactant: O=C(O)/C=C/C1CCOCC1
Reactant: Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 3, STEP B, the title compound was prepared from 2-nitro-4-(2-trifluoromethyl-pyridin-4-yl)-phenylamine (84.5 mg, 0.298 mmol, as prepared in the previous step) and (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2, A3), 60.5 mg, 0.388 mmol) and was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:26]([NH:30][CH2:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:34]([CH3:45])[CH:33]=1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH2:26]([N:30]([CH2:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:34]([CH3:45])[CH:33]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(-c2ncnc(Cl)c2C)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Temperature: 100 °C
Yield: 18.5 %

Procedure:
A mixture of 4-chloro-6-(4-methoxyphenyl)-5-methylpyrimidine (0.164 g, 0.7 mmol), diisopropylethylamine (0.24 mL, 1.4 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.29 g, 1.05 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature. The residue was dissolved in CH2Cl2 (50 mL), the organic solution was washed water (20 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 3:17–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (62 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][C:29]=4[O:41][CH3:42])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:43])[N:15]=1)=[O:13])[CH3:2].O>CN(C)C=O.FC(F)(F)C(O)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:40]=[CH:39][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=4[O:41][CH3:42])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:43])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C(=O)OC(C)(C)C)cc3OC)nc1-2
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-8-yl}amino)-3-methoxybenzoate (500 mg, 0.857 mmol) in dimethylformamide (8 mL), trifluoro acetic acid (0.600 mL), were added. The mixture was stirred at room temperature overnight. Water was added and the mixture extracted with ethylacetate. The organic solvent evaporated to dryness. To give 450 mg of the title compound in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:26])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CS(C)=O>[CH2:41]([O:40][C:38]([CH2:37][C:8]1([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:27][CH2:28][CH3:29])[C:7]1=[O:26])=[O:39])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: CCOC(CN1C(=O)C(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1(NC(=O)Nc2ccc(C)cc2)C(=O)N(CC(OCC)OCC)c2ccccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 7.50 g of (RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 100 ml of dry dimethyl sulfoxide was added 20 ml of a 1M solution of potassium t-butoxide in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere, followed by stirring for 30 minutes. To the mixture was added dropwise a solution of 2.30 ml of ethyl bromoacetate in 20 ml of dry dimethyl sulfoxide, followed by stirring at the same temperature for 30 minutes. A sodium chloride aqueous solution was added thereto, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 8.21 g (90%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)-pyrrolidine-1-carboxylate (2.3 g, 7.0 mmol) and NBS (1.48 g, 8.39 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Solvent was removed to afford the crude product, which was purified by reverse phase Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to give tert-butyl 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (2.28 g, 75% yield) as white solid. LCMS (ESI) m/z: 332.1 [M+H+]. 1H-NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 3.88 (s, 3H), 3.75-3.61 (m, 3H), 3.52 (s, 1H), 3.38 (s, 1H), 2.48 (s, 1H), 2.15 (s, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:3].[OH-].[K+].OS([O-])(=O)=O.[K+].C(Cl)Cl>O1CCCC1.O>[CH3:3][C:2]([CH3:29])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: COC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 4 h
Yield: 103.4 %

Procedure:
The title product of Example 1 (25.0 g, 58.6 mmol) dissolved in 150 ml of tetrahydrofuran (THF) was combined with a solution of potassium hydroxide (KOH, 7.7 g, 0.12 mmol) dissolved in 375 ml of water. After this reaction was stirred for 4 h, it was poured into a mixture of 2.5N KHSO4 (400 ml) and CH2Cl2 (500 ml). The organic layer was separated and the aqueous (pH2) was extracted 3×100 ml of CH2Cl2. The combined organics were washed with 150 ml of brine, dried over Na2SO4, and stripped of all solvent under reduced pressure. The residue, after in vacuo drying, yielded 25 g of the title product as a white powder. This material was used without further purification.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH:24]C(OCC3C=CC=CC=3)=O)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[CH:1]([OH:3])=[O:2].[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH2:24])[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a 4.5% solution of 90% aqueous formic acid in methanol was added 120 mg of 10% palladium on carbon catalyst under nitrogen. To this suspension was added 150 mg of 6-phenyl-4-benzyloxycarbonylamino-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepin. The reaction mixture was stirred under nitrogen at 23° C. for 1.5 hours and filtered through Celite. The filtrate was concentrated under reduced pressure and azeotropically dried with toluene to yield the title compound.