Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O)(=O)[CH3:25].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:24][CH3:25])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.11 g) in 1,2-dichloroethane (5 mL) was added 18 μL of acetic acid, 26 μL of acetaldehyde, and 0.10 g of NaBH(OAc)3. The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (1% 2 M NH3 in MeOH/CH2Cl2) afforded 0.02 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.02 g of the corresponding HCl salt. MS (ESI): exact mass calculated for C22H23ClN2, 350.15; found, m/z 351.2 [M+H]+, 353.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.17-5.13 (m, 2H), 4.48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23 (m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:25]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:25]=1
Reactant: Cc1ccc(-n2nc(C)cc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1ccc(-n2nc(C)cc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-Methyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=1.27 min; [M+H]+=475.2.
Reaction SMILES: [C:1]([C@:3]12[CH2:28][C:27](=[O:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=1[CH2:5][CH2:4]2)#[N:2].[BH4-].[Na+]>>[C:1]([C@:3]12[CH2:28][C@@H:27]([OH:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=1[CH2:5][CH2:4]2)#[N:2].[C:1]([C@:3]12[CH2:28][C@H:27]([OH:29])[CH2:26][CH2:25][C@:24]1([CH3:30])[C:23]1[CH2:22][CH2:21][C@@:20]3([CH3:31])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@H:11]([CH3:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=1[CH2:5][CH2:4]2)#[N:2]
Reactant: C[C@H](CC1CCCCC1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H](Cc1ccccc1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@]1(C#N)CC3
Product: C[C@H](Cc1ccccc1)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@]1(C#N)CC3

Procedure:
152 mg (20R)-5-cyano-21-cyclohexyl-20-methyl-5α-pregn-8-en-3-one were treated with 50 mg sodium borohydride as described in example 58b. After column chromatography 36 mg (20R)-5-cyano-21-phenyl-20-methyl-5α-pregn-8-en-3β-ol and 46 mg (20R)-5-cyano-21-phenyl-20-methyl-5α-pregn-8-en-3α-ol were isolated.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[F:18][C:19](=[CH2:22])[CH:20]=[O:21]>O1CCCC1>[F:18][C:19]([CH:20]([OH:21])[C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[CH2:22]
Reactant: C=C(F)C=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(F)C(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran, and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under a stream of a nitrogen gas, 81.13 ml of a 1.5M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After aging the reaction solution at -50° C. for 30 minutes, 9.01 g (0.122 mole) of 2-fluoroacrolein was added dropwise at -50° C. or less. After the reaction mixture was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 11 g of 2-fluoro-3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 86° C.).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[N:13]=[C:12]([N:14]([CH3:1])[C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(C)oc2cc(Nc3ccnc(Cl)n3)ccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Potassium carbonate (0.75 mmol) was added to a solution of 6-(2-chloropyrimidin-4-ylamino)-N,2-dimethylbenzofuran-3-carboxamide (0.5 mmol) in 5 ml acetone. After 15 mins, methyl iodide (0.5 mmol) was added. The reaction mixture was stirred at 60° C. for 2 days before the solvent was removed in vacuo. THF was added and the residue was filtered and subjected to column chromatography to provide the 6-((2-chloropyrimidin-4-yl)(methyl)amino)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 22%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Reactant: C1CCCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]#[C:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH2:43][CH2:42]1>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:41]1[CH2:42][CH2:43][CH:44]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])[CH2:45][CH2:46]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C(O)C#CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
After 3-((6-chloronaphthalen-2-yl)sulfonyl)propinoic acid (0.30 g), HOBt (0.23 g) and WSC (0.29 g) were dissolved in DMF (10 mL), 1-(piperidin-4-yl)-2-pyrrolidinone (0.17 g) and triethylamine (0.10 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.17 g, 39%) as a colorless powder.
Reaction SMILES: [Cl-].[C:2]1([N:8](C2C=CC=CC=2)C([N+]2C=CC=CC=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46](O)=[O:47])[CH:43]=2)[NH:38][CH:37]=1.C(N(CC)CC)C>O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46]([NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:47])[CH:43]=2)[NH:38][CH:37]=1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
An ice-cold solution of diphenylamino carbonyl pyridinium chloride (3.5 g) in water (35 ml) was added dropwise to a mixture of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (3.5 g), triethylamine (2.8 ml) and ice-water (70 ml) with rapid stirring over 15 min. After stirring the mixture for a further 10 min. it was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with water (1×50 ml), dried (Na2SO4), and evaporated in vacuo to give an orange solid (3.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:37]([CH3:36])(=[O:39])=[O:38])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and methanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspension was stirred for 18 h at ambient temperature. Further N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol) and methanesulfonyl chloride (54 μL, 0.689 mmol) were added and stirred was continued for 24 h at 50° C. The reaction mixture was then extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (34 mg, 14%) as a light yellow solid. MS: m/e=427.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[C:11]([C:15](Cl)=[N:16][OH:17])=[N:12][O:13][N:14]=1.C(N(CC)CC)C>C(O)C>[NH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[N:12][O:13][N:14]=1
Reactant: Nc1nonc1C(Cl)=NO
Reactant: Nc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nonc1C(=NO)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 3-fluoroaniline (36 μL, 0.37 mmol) in ethanol (0.5 mL) was treated with a solution of 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (50 mg, 0.31 mmol) in ethanol (1.5 mL) followed by triethylamine (51 μL, 0.37 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h and purified by preparative LCMS to give the desired product (21 mg, 29%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>>[ClH:34].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-cyano-3-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (250 mg; 0.68 mmol, prepared in accordance with Example 154) in dichloromethane (5 mL) is added trifluoroacetic acid (1.5 mL) and the reaction mixture is stirred at room temperature for 30 minutes. All volatiles are then removed under high vacuum and the residue is taken up with diethyl ether and concentrated again. The residue is dissolved in a minimum amount of dioxane and a 4 molar solution of hydrochloric acid in dioxane is added. The precipitate formed is collected, washed with diethyl ether and dried under high vacuum to afford the desired compound (225 mg; 0.74 mmol).
Reaction SMILES: C1([C:7]2([C:17](O)=[O:18])[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)N2)C=CC=CC=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.[NH2:54][C:55]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([CH2:59][CH3:60])[C:56]([NH2:58])=[O:57]>C(Cl)Cl>[C:56]([C:55]([NH:54][C:17]([C:7]1[C:37]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:34]=[C:15]([C:14]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)=[O:18])([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:59][CH3:60])(=[O:57])[NH2:58]
Reactant: CCC(N)(C(N)=O)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)C=Cc2ccccc2N1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cc(-c2ccccc2)nc2ccccc12)(C(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a solution of 2-phenylquinolinecarboxylic acid (600 mg, 2.4 mmol) in 10 mL of CH2Cl2 containing 1 mL of triethylamine is added BOP (1.3 g, 2.9 mmol) followed by 2-amino-2-phenylbutanamide (500 mg, 2.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is diluted with 20 mL of CH2Cl2, then washed with aqueous Na2CO3, aqueous citric acid and brine. After drying over Na2SO4, the solvent is evaporated to afford N-(1-Carbamoyl-1-phenylpropyl)-2-phenyl-4-quinolinecarboxamide (700 mg) as a pale yellow foam.
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4].[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>C[O-].[Na+].CO>[OH:20][C:6]1[C:7]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:11][C:8]=2[CH:9]=[N:10][C:5]=1[C:3]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:4]
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Yield: 89.7 %

Procedure:
7-Hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (100 mg, 0.37 mmol), and glycine (583 mg, 7.77 mmol) were suspended in 14.8 mL of 0.5N sodium methoxide in methanol. The reaction mixture was heated at reflux temperature overnight, then cooled, and concentrated. The residue was dissolved in water (30 mL), and the solution was acidified to pH 1-2 with 2N HCl, and subsequently extracted with ethyl acetate. The combined organic layers were dried, and concentrated to produce 104 mg of the title compound as a yellow solid. MS: (+) m/z 314.0 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:11]1([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.[C:28](OC(C)(C)C)(=[O:33])[CH2:29][C:30]([O-])=[O:31].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:24]([C:23]4[CH:26]=[CH:27][C:20]([N:17]5[CH2:18][CH2:19][N:14]([CH:11]6[CH2:13][CH2:12]6)[CH2:15][CH2:16]5)=[CH:21][CH:22]=4)[C:30](=[O:31])[CH2:29][C:28]3=[O:33])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(N2CCN(C3CC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCN(C3CC3)CC2)cc1
Reaction time: 48 h

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.86 g, 6.5 mmol), 4-(4-cyclopropylpiperazin-1-yl)benzaldehyde (1.5 g, 6.5 mmol), mono-tert-butyl malonate (1.04 g, 6.5 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.02 g, 6.5 mmol) with stirring for 2 days and sodium tert.-butoxide (0.60 g, 5.4 mmol) according to method 5.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].Cl.[CH3:16][C@@H:17]([NH2:22])[C:18]([F:21])([F:20])[F:19].C(O)(=O)C>CO>[CH3:16][C@@H:17]([NH:22][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: C[C@@H](N)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of 4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37 mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75 mmol). Stir the mixture at room temperature overnight. Partition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL) and extract the aqueous layer twice with DCM. Dry the combined organic extracts over MgSO4, concentrate in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:36]=[C:10]3[C:11]([C:15]4[CH:35]=[CH:34][C:18]([CH2:19][N:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]5[CH3:33])=[CH:17][CH:16]=4)=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][C@@H:21]1[CH2:22][NH:23][CH2:24][CH2:25][N:20]1[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[C:10]3[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH:36]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:35][CH:34]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1

Procedure:
(R)-tert-Butyl 4-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-3-methylpiperazine-1-carboxylate (162 mg, 0.33 mmol) was stirred in DCM (2 mL) and TFA (0.3 mL) at room temperature for 2 h. The reaction mixture was concentrated in vacuo and loaded onto an SCX column in DCM. MeOH (20 mL) was passed through the column and the compound was eluted with (7 N NH3 in MeOH in MeOH) (1:5) (50 mL). The filtrate was concentrated in vacuo to give (R)—N-(4-(4-((2-methylpiperazin-1-yl)methyl)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-:11].[Na+].[CH3:13][NH2:14]>>[CH3:9][C:4]1[N:5]=[C:6]([NH:14][CH3:13])[N:7]=[C:2]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: CN
Agent: [Na+]
Product: CNc1nc(C)nc(OC)n1

Procedure:
reacting the 2,4-dichloro-6-methyl-1,3,5-triazine with sodium methoxide and monomethylamine to form 2-methyl-4-methylamino-6-methoxy-1,3,5-triazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27](Cl)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH2:38]([NH2:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])=[CH:11][C:10]=1[S:27]([NH:43][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CN
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(S(=O)(=O)NCC(C)(C)C)c1
Reaction time: 6 h

Procedure:
A solution of the title E compound, 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-benzenesulfonyl chloride (1.12 g, 2.5 mmol) in 20 mL of CH2Cl2 is treated sequentially with N-methylmorpholine (NMM; 550 mL, 5 mmol) and neopentylamine (442 mL, 3.75 mmol) at RT. After 6 h, the mixture is partitioned between water and EtOAc, and the organic solution is washed with aqueous 1N HCl and brine, dried over anhydrous Na2SO4 and concentrated to afford 2-benzyloxy-5-(2,6-dimethyl-4-nitrophenoxy)-N-(2,2-dimethylpropyl)benzenesulfonamide: NMR (CDCl3) 0.78 (s, 9H), 2.22 (s, 6H), 2.58 (d, 2H, J=7.5), 4.82 (t, 1H, J =7.5), 5.18 (s, 2H), 6.88 (dd, 1H, J=9, 3.7), 7.03 (d, 1H, J=9), 7.33-7.51 (m, 6H), 8.04 (s, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]2=[CH:26][CH:25]=[CH:24][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.