Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[N+:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[C-:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:18]=[N:17][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of ethyl isocyanoacetate and subsequently with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at room temperature for 48 hours. After distillation of the solvent, the residue is extracted with ethyl acetate/water. The crude product obtained after evaporation is chromatographed on a 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate/hexane there is obtained ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazole-carboxylate in the form of yellow crystals of m.p. 109°-110°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[C:18][CH3:19])[CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[CH2:22]([N:29]([CH2:33][CH2:34]Cl)[CH2:30][CH2:31]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:33][CH2:34][C:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[C:18][CH3:19])[CH:10]=2)(=[O:7])=[O:8])([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC#CCOc1cccc(S(=O)(=O)CC(=O)OCC)c1
Agent: Cl
Product: CC#CCOc1cccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)c1
Yield: 63 %

Procedure:
Ethyl 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[3-(2-butynyloxy)phenyl]sulfonyl}acetate (3 g, 10.1 mmol) and benzyl-bis-(2-chloro-ethyl) amine hydrochloride (2.88 g, 10.7 mmol); 2.91 g yellow oil. Yield 63%; MS: 456.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].Cl.[NH2:24][C@H:25]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33])[CH2:26][CH2:27][OH:28]>ClCCl.C(N(CC)C(C)C)(C)C>[OH:28][CH2:27][CH2:26][C@@H:25]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33])[NH:24][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: N#Cc1cccc([C@@H](N)CCO)c1
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2cccc(C#N)c2)=NS(=O)(=O)C1(C)C
Yield: 59.3 %

Procedure:
100 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 97 mg of 3-((S)-1-amino-3-hydroxypropyl)benzonitrile hydrochloride were dissolved in 5 ml of dichloromethane and 0.25 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane, and washed with 10 ml of 10% aqueous ammonia solution and with 10 ml of 1 N aqueous hydrochloric acid. The two aqueous phases were extracted once again with 20 ml of ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (66 mg) was thus obtained with a molecular weight of 365.5 g/mol (C17H23N3O4S); MS (ESI): m/e=366 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:12]([CH3:13])[N:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(Cl)cc3=O)ccc2nn1C1CC1
Temperature: 45 °C
Reaction time: 22 h

Procedure:
To a suspension of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (118 g) in DMF (2 L) was added phosphorus oxychloride (46.9 ml) at room temperature, and the mixture was stirred under an argon atmosphere at an inside temperature of 45° C. for 22 hr. The reaction mixture was poured into ethyl acetate (3 L), and washed with saturated aqueous sodium hydrogen carbonate (1.5 L). The obtained aqueous layer was extracted twice with ethyl acetate (2 L and 1 L). The organic layer was washed with aqueous sodium sulfite solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a 1:1 mixed solvent (1.1 L) of ethyl acetate and tetrahydrofuran with heating, and the mixture was filtered through NH silica gel (750 g). The eluate was concentrated under reduced pressure, and the obtained residue was solidified with diisopropyl ether to give the title compound (73.2 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>C(Cl)Cl>[CH2:34]([O:33][C:31]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A 1.5 dram vial equipped with a flea stirbar was charged with (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt (30 mg, 0.10 mmol), i-Pr2NEt (72 μL, 0.4 mmol) and CH2Cl2 (1 mL). Ethyl chloroformate (15 mL, 0.123 mmol) was added. The mixture was stirred at rt overnight and applied to a 10-mL Chem-Elut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by prep HPLC to afford (R)-(2-adamantyl) 3-(ethoxycarbonylamino)pyrrolidine-1-carboxylate (24 mg, 71%). LC-MS Method 1 tR=1.88 min, m/z=337; 1H NMR (CDCl3) 1.27 (t, 3H), 1.58 (d, 2H), 1.70-2.00 (13H), 2.19 (m, 1H), 3.13 (1H), 3.26 (dd, 1H), 3.59 (m, 2H), 3.70 (m, 1H), 4.17 (d, 1H), 4.29 (1H), 4.78 (1H), 4.82 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:13][O:14]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH:13]=[O:14]
Reactant: COc1ccc(C)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methylanisole (12.2 g., 0.1 mole) in 300 ml. of methylene chloride was cooled to 0° C. Titanium tetrachloride (3.8 g., 0.2 mole) was added followed by the dropwise addition of 1,1-dichloromethyl methyl ether (13.8 g., 0.12 mole) over 3 minutes. After stirring for 30 minutes at 0° C., the reaction mixture was poured into 600 ml. of water. The aqueous phase was extracted with two further portions of methylene chloride. The combined organic phase/extracts was washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 2-methoxy-5-methylbenzaldehyde as an oil [15 g., 100%; ir (CH2Cl2) 1678, 1608, 1488 cm-1 ].
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 48.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and acetic anhydride (0.52 mL, 5.5 mmol) in pyridine (14 mL) provided N-(6,7,8,9-Tetrahydro-dibenzofuran-2-yl)-acetamide (0.56 g). Mp 195.5-197.5° C.; MS m/z 230 ([M+H]+); Anal. Calcd. for C15H17NO2: C, 73.34; H, 6.59; N, 6.11; Found: C, 73.45; H, 6.54; N, 6.06.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[C:7]1[N:8]=[C:9]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[N:21]=2)[N:10]=[N:11][C:12]=1[C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=O.[NH3:38]>C(#N)C>[CH3:19][C:13]1([CH3:18])[C:12]2[N:11]=[N:10][C:9]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:34])([F:35])[F:33])[N:21]=3)=[N:8][C:7]=2[NH:38][C:14]1=[O:16]
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 ml of phosphoryl chloride were added to 263 mg (0.571 mmol) of the compound from Example 16A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 38 ml of acetonitrile and, with ice-cooling, stirred into 24 ml of concentrated aqueous ammonia solution (33% strength). The mixture was stirred at RT for 2 days. The reaction mixture was then concentrated. The residue was taken up in water and ethanol and stirred at RT for 1 h. The precipitate formed was filtered off with suction and washed with water and ethanol. This residue was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 119 mg of the title compound (49% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([O:18][CH3:19])[C:13](=O)[NH:14][C:15](=O)[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([N:8]1[CH2:12][C@:11]2([O:18][CH3:19])[C@@H:10]([CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CO[C@]12CNC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (cis)-5-benzyl-3a-methoxytetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (400 mg, 1.54 mmol) in diethyl ether (7 mL), under nitrogen, was added LAH (7.92 mL, 1.0 M in diethyl ether) to form a white suspension that was stirred at ambient temperature for 21 hrs. The reaction was then cooled to 0° C. and quenched by the addition of water (0.3 mL), 15% NaOH (0.3 mL) and water (0.9 mL), as described by Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis Vol. 1, Wiley, New York 1967, pp 581-595. The mixture was filtered and washed with EtOAc (100 mL). The filtrate was concentrated with toluene to give the crude title compound as a clear oil that was carried forward to the next step without further purification assuming quantitative yield. m/z (APCI+) for C14H20N2O 233.20 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[BH4-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH:11]([C:10]#[N:14])[C:12]#[N:13]
Reactant: O=Cc1cccc(Br)c1
Reactant: N#CCC#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
First, 0.93 g of 3-bromobenzaldehyde and 0.33 g of malononitrile were dissolved in 5 ml of ethanol, to which 1.5 ml of water was added, followed by stirring at room temperature for 4 hours. Then, after cooling at −5° C., a suspension of 57 mg of sodium borohydride in 3 ml of ethanol was added dropwise, followed by stirring at −5° C. for 30 minutes. 10% hydrochloride acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.94 g of (3-bromobenzyl)malononitrile (the intermediate (28)).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH3:36])[CH2:31]2>CN(C=O)C>[CH3:36][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[CH:35][C:26]=2[NH:25][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[C:3]([O:13][CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:31]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
5-Bromo-2,4-dimethoxybenzoic acid (0.296 g, 1.1 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (0.186 g, 0.94 mmol) and 1-hydroxybenzotriazole (0.144 g, 0.94 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature under argon for 25 mins before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.153 g, 0.94 mmol) was added. The mixture was then stirred overnight under argon at room temperature. The DMF was removed in vacuo and the residue taken up into ethyl acethate and washed with water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate/hexane to afford the title compound as a solid (0.106 g)
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][NH2:16]>ClCCl.C(O)C>[CH3:15][NH:16][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNCc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
10 g of 4-Biphenylcarbaldehyde and 40 ml of 33% ethanolic methylamine are stirred overnight at room temperature with a 4 Å molecular sieve. The mixture is filtered and concentrated under vacuum. The residue is treated in 60 ml of ethanol with 2 g of sodium borohydride and stirred for 3 hours. The solvent is removed under vacuum, the residue partitioned between ether and water and the organic phase dried and concentrated. The pure base is obtained as an oil following chromatography on silica gel with dichloromethane/ethanol=9/1 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]1([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=[O:29])=[O:12].C(O)C>[C].[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([NH:13][C:14]1([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]1=[O:29])=[O:12]
Reactant: CCOC(=O)CCC1(NC(=O)/C=C/c2ccccc2OC)C(=O)N(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCC1(NC(=O)CCc2ccccc2OC)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 719 mg of ethyl 3-[2,3-dihydro-3-[(E)-3-(2-methoxyphenyl)-2-propenoylamino]-2-oxo-1-phenyl-1H-indol-3-yl]propionate, 20 ml of ethanol and 6 ml of tetrahydrofuran was hydrogenated on 100 mg of 10% palladium-carbon under hydrogen gas atmospheric pressure while stirring overnight. The catalyst was filtered off, and the solvent was removed from the filtrate by evaporation to afford 700 mg of ethyl 3-[2,3-dihydro-3-[3-(2-methoxyphenyl)propanoylamino]-2-oxo-1-phenyl-1H-indol-3-yl]propionate as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:23])[CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C.O>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][O:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:30][CH:29]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc3nc(C)cc(N4CCC(c5ccccc5)C4)c3c2)cc1
Reaction time: 18 h

Procedure:
2-Methyl-4-(3-phenylpyrrolidin-1-yl)quinolin-6-ol (0.05 g; see Example 42 below) was stirred with sodium hydride (60% dispersion in mineral oil; 0.035 g) in DMF (2 mL) for 15 minutes, after which 4-methoxybenzyl bromide (0.12 g) was added. After 18 hours, the reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to give a brown oil. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave the title compound as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.[NH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1F)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of 5-(2-fluorophenyl)-1,3-cyclohexanedione (2.0 g), 3-aminopropan-2-ol (0.95 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the solution were added 2-bromomesitylene (1.9 g), tetrakistriphenylphosphine palladium (0.28 g) and potassium carbonate (2.7 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (0.96 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0 g, 53.7 mmol) in MeOH (100 mL) was added sodium borohydride (2.2 g, 59.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before it was quenched with water (5.0 mL). Evaporation of solvents afforded light yellowish oil which was re-dissolved in EtOAc and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (9.6 g, 95%) as colorless oil. MS: 188.0 & 190.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)C(=O)OC(C)(C)C)[N:5]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3\[NH:24][C:25](=[O:29])[NH:26][C:27]\3=[O:28])=[C:4]2[N:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[OH:39])[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][C:2]1[CH:7]=[C:6]([NH:8][CH:16]2[CH2:18][CH2:17]2)[N:5]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3\[NH:24][C:25](=[O:29])[NH:26][C:27]\3=[O:28])=[C:4]2[N:3]=1)[C:34]#[N:35]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(/C=C3\NC(=O)NC3=O)cnn12)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)c(Cl)c1
Reaction time: 24 h
Yield: 57.4 %

Procedure:
(Z)-tert-butyl 5-chloro-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (0.6 mL). 3-chloro-4-hydroxybenzonitrile (41 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) were added. After 24 h, H2O (3.5 mL) was added to the reaction and the bright yellow precipitate was filtered and dried. The crude solid was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O (3 mL) and filtered to provide (Z)-3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzonitrile (45 mg, 57% over two steps) as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([CH3:17])=[CH:16][C:3]=12.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([CH3:17])=[C:16]([Br:18])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(C)cc2c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(C)c(Br)c2c1N
Reaction time: 1 h
Yield: 111.6 %

Procedure:
To a stirred solution of ethyl 4-amino-2,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (6.44 g, 25.7 mmol) (Description 5) in DCM (110 mL), was added N-bromosuccinimide (9.16 g, 51.5 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated and the solid that precipitated was filtered and washed with DCM (3×10 mL), to afford the title compound (9.44 g). LCMS (A) m/z: 329/331 [M+1]+, Rt 1.22 min (acidic).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-methoxyaniline as the starting materials.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([NH2:21])=[O:2])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(N)=O
Yield: 46.6 %

Procedure:
The process was carried out as was Example 45, starting with 2.8 g of the compound of Example 25, 2.5 g of carbonyldiimidazole and 4 ml of ammonium hydroxide. The product was recrystallized from toluene and then from ethanol to obtain 1.3 g of the desired product, m.p. 143°-145°.