Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8].[NH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:17]=1[C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:33][C:32]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:15]=[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:17]=12
Reactant: N#Cc1c(-c2cccs2)nn(-c2ccccc2)c1N
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc2c(c(-c3cccs3)nn2-c2ccccc2)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 85.7 %

Procedure:
A dimethylsulfoxide (20 ml) solution of 10.0 g (70 mmol) of dimethyl acetylenedicarboxylate was dropwise added to a mixture comprised of 2.66 g (10 mmol) of 5-amino-1-phenyl-3-(thiophen-2-yl)pyrazole-4-carbonitrile, 27.6 g (200 mmol) of anhydrous potassium carbonate and 300 ml of dimethylsulfoxide, while cooling with ice, over a period of 30 minutes, and then stirred for further 60 hours at room temperature. During the stirring, the reaction liquid was changed from brown to greenish brown. After the reaction, the liquid reaction mixture was poured into 500 ml of water with ice and stirred for 30 minutes at room temperature. The blackish brown solid thus precipitated was taken out by filtration, dried in air and added to 20 ml of methanol. The white crystals thus formed were taken out by filtration and recrystallized from methanol to obtain 3.50 g of the entitled product as colorless crystals having a melting point of 178° to 180° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].C([O-])(=O)C.[Na+].CN([CH:20]=[C:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=O)C>CCCCO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[CH:20]=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Product: O=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 55.9 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)hydrazine hydrochloride (6.78 g, 31.8 mmol) and anhydrous sodium acetate (2.60 g, 31.8 mmol) in n-BuOH (20 mL) is slowly added to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (5.32 g, 31.8 mmol) in n-BuOH (100 mL) and acetic acid (5 mL). The resulting mixture is heated to reflux during 2 hours, effecting follow-up of the reaction by TLC. The solvent is evaporated at reduced pressure, the residue is diluted in AcOEt and washed with H2O. The solvent is next evaporated, and the crude is purified by silica-gel chromatography, to obtain 1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (5.0 g, 17.79 mmol, 56%, orange solid).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(N5CCNCC5)cc4)ccc3c1)n2C1CCCCC1
Yield: 91 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-piperazin-1-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (120 mg, 91% yield). MS: 532.21 (M+H+); HPLC Procedure A, retention time=7.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Cl:22])[N:3]=1.Cl>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:22])[CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Yield: 93.4 %

Procedure:
1.25 g (0.0035 mol) of N-[4-(2,6-dichloro-pyridin-4-ylsulfamoyl)-phenyl]-acetamide were dissolved in 35 ml of 1N NaOH and boiled at reflux for 2 hours. After cooling the mixture was adjusted to pH 6 with 2N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed well with water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:2→1:1. There were obtained 1.04 g (93%) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide as white crystals; m.p.: 209-211° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[N:8]=1>O1CCCC1>[Cl:14][C:9]1[CH:10]=[C:11]([Cl:13])[N:12]=[C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Clc1cc(Cl)nc(N2CCCC2)n1
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
After dropping 23.7 ml (286.6 mmoles) of pyrrolidine to a mixture containing 25.0 g (136.3 mmoles) of 2,4,6-trichloropyrimidine in 200 ml of tetrahydrofuran at -20° C. within about 30 minutes, the cooling is stopped and after stirring for an additional 30 minutes the reaction mixture is evaporated. After distributing the residue between 500 ml of chloroform and 50 ml of 10% sodium hydroxide solution, the organic phase is separated, washed 4 times with 150 ml of water each, then dried and evaporated. The residue is subjected to chromatography on a silica gel column. By using a 19:1 hexane/ethyl acetate mixture as eluent the eluate is evaporated and the evaporation residue is recrystallized from hexane to give 7.51 g (25.27%) of 4,6-dichloro-2-pyrrolidinopyrimidine, m.p. 95°-98° C.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)=[O:7].[Cl-].[NH4+]>O1CCCC1>[OH:7][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(O)C(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
(a-1) To a stirred and refluxed Grignard complex previously prepared starting from 110.7 parts of 2-bromopropane, 21.75 parts of magnesium and 900 parts of dry tetrahydrofuran were added dropwise 50 parts of N-(4-formylphenyl)acetamide at <30° C. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was hydrolysed with a mixture of ammonium chloride and crushed ice and the product was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated to dry, yielding 63.5 parts (100%) of N-[4-(1-hydroxy-2-methylpropyl)phenyl]acetamide as a residue (int. 101).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:23][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])=[O:25])[CH2:11][CH2:12]1
Reactant: O=C(CCl)Nc1ccccc1C(F)(F)F
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 41 mg (75%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.73 (m, 2H), 8.15 (d, J=5 Hz, 1H), 8.22 (d, J=6 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>C1COCC1>[F:15][C:16]1[CH:17]=[C:18]([C:19]2[O:20][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(F)c(F)c1
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a well stirred solution of the methyl isocyanoacetate (2 g, 20.2 mmol) in THF (3 mL), triethyl amine (8.4 mL, 6.06 mmol) was added and the reaction mixture was stirred for 15 minutes. Then 3,4-difluorobenzoylchloride (2.5 mL, 20.20 mmol) was added neat over a period of five minutes and the reaction mixture was allowed to stir at room temperature for 48 hours. It was then concentrated, partitioned between ethyl acetate (50 mL) and water. The organic layer was washed with 10% NaOH solution (20 mL), dried over sodium sulfate, filtered and concentrated to yield 3.8 g (79%) of a brown solid which was recrystallized from hexanes: 1H-NMR (CDCl3) δ3.74(s, 3H), 7.47-7.50 (m, 1 H), 7.92 (s, 2 H), 8.01-8.10 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Cl)cc1Br
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Cl)CCC1

Procedure:
using isopropyl 2-bromo-4-chloro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2-bromo-4-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:22])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1sc(CCC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 1.4 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 20 ml of dimethylformamide are added 0.5 g of N-hydroxybenzotriazole and 0.35 g of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.9 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 3 hours and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off, the filtrate is concentrated under reduced pressure and then the residue is dissolved in 100 ml of chloroform. The solution is washed with 50 ml of 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 1 g of 3-[4 -(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid morpholide as colorless crystals, melting at 162°-163° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](I)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17].C(N(C(C)C)C(C)C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]3[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]3)=[CH:20][C:19]=1[F:33])=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a sealed flask was added 4-benzyl-2-iodobenzenamine (0.20 g, 0.65 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.32 g, 1.3 mmol) in THF (15 mL). To this solution was added PdCl2(PPh3)2 (0.045 g, 0.065 mmol), CuI (0.025 g, 0.13 mmol), and ethyldiisopropylamine (0.90 mL, 5.2 mmol). The flask was flushed with Ar, sealed and placed in a preheated oil bath at 100° C. for 3 h. The mixture was concentrated under reduced pressure to afford a dark oil which was adsorbed onto silica and purified (30% EtOAc/hexanes to 100% EtOAc) to afford title compound as a yellow oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cnc(NC(=O)C(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
5-Methylthiazol-2-amine (5.71 g, 50.0 mmol) and pivaloyl chloride (6.78 mL, 55.0 mmol) were mixed in anhydrous acetonitrile (80 mL) and treated with triethylamine (14.0 mL, 100 mmol) resulting in an exotherm. After 15 minutes, the warm suspension was cooled for 5 minutes with a water bath. The solids were collected by filtration and rinsed with more acetonitrile. The filtrate was partially concentrated and the solids which precipitated were also collected by filtration and rinsed with acetonitrile. The two crops were combined and rinsed with water, and when solids precipitated from the filtrate they were collected by filtration and added to the previously collected material. The crude product was washed with 1:1 dichloromethane/hexanes and dried under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-[(4-tert-Butylcyclohexylimino)methyl]benzoic acid methyl ester (21.0 g, 69.2 mmol) was suspended in methanol (300 mL), and acetic acid (50 mL) was added. To the resulting clear solution was added sodium cyanoborohydride (3.5 g, 55.5 mmol), and the mixture was stirred at ambient temperature for 30 min. The reaction volume was then reduced to one third by rotary evaporation, and ethyl acetate (500 mL) was added. The organic phase was washed with sodium carbonate solution (5%, 500 mL), and dried with Na2SO4. The solvent was removed by rotary evaporation to leave the title material as a white crystalline solid sufficiently pure for further reactions. Yield: 21.1 g (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH2:5]
Reactant: [H][H]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O

Procedure:
In a mixture of 50 ml of methanol and 5 ml of acetic acid was dissolved 3 g of benzyloxycarbonyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester and after addition of 500 mg of palladium black, the mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and to the residue was added 100 ml of ethyl ether-petroleum ether (1:5). The mixture was allowed to stand in a refrigerator overnight and the resulting precipitate was collected by filtration and dried. Yield 1.4 g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].B.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][OH:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: B
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(methylsulfonyl)benzoic acid (1.2 g, 6.0 mmol) in THF (30 mL) at 0° C., is added equimolar amounts of borane (6.0 mL of a 1.0 M solution in THF) and boron trifluoride diethyl etherate (0.8 mL, 6.0 mmol). The reaction is allowed to warm to ambient temperature overnight, and then quenched by pouring into a mixture of ice and solid NaHCO3. Following extraction with EtOAc, the organic layer is washed with brine and dried over Na2SO4. Removal of solvent affords the product as a colorless oil: MS (M+NH4)+=204.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: NCc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=225 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.49 (s, 1 H), 8.14 (s, 1 H), 8.03-8.10 (m, 2 H), 7.66-7.73 (m, 2 H), 7.47-7.56 (m, 2 H), 7.43-7.44 (m, 1 H), 7.33-7.40 (m, 1 H), 4.10-4.18 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:12](Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>[OH-].[Na+]>[CH2:12]([NH:1][CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NCC1(C(=O)O)CCCCC1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC/C=C\C/C=C\CCCCCCCCNCC1(C(=O)O)CCCCC1
Temperature: 25 °C

Procedure:
5 grams of aminomethylcyclohexanecarboxylic acid were dissolved in 50 cm3 of 6% sodium hydroxide. This solution was stirred vigorously and maintained at 10° C while 10 grams of linoleyl chloride were added drop by drop. The stirring was maintained for 1 hour at ambient temperature. The precipitate obtained on centrifuging was washed twice with acetone and allowed to dry.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[CH:18]3[CH:21]([CH2:22][C:23]=2[S:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH:20]([CH:31]([OH:33])[CH3:32])[C:19]3=[O:34])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:28]([NH:27][CH2:26][CH2:25][S:24][C:23]1[CH2:22][CH:21]2[CH:18]([C:19](=[O:34])[CH:20]2[CH:31]([OH:33])[CH3:32])[C:17]=1[C:15]([OH:16])=[O:14])(=[O:30])[CH3:29]
Reactant: CC(=O)NCCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)C2C(=O)C(C(C)O)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)C(C(C)O)C2C1
Yield: 91.8 %

Procedure:
A solution of 50 mg of 3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester and 25 μL of anisole in 1.5 mL of trifluoroacetic acid was stirred at room temperature for 10 min. The reaction mixture was evaporated to dryness, and trituration of the residue with ether afforded 30 mg (95%) of 3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless, hydroscopic crystals. IR (Nujol mull) 1550, 1660, 1775 cm-1 ; NMR (400 MHz; acetone-d6): δ 1.24 (3H, d, J=6.5), 1.94 (3H, s), 2.98 (1H, m), 3.03 (2H, t, J=7), 3.14 (1H, ddd, J=18, 3.4, 1.2), 3.22 (1H, ddd, J=5.6, 3.9, 3.2), 3.35 (1H, dd, J=8.5, 1.7), 3.40 (2H, t, J=7), 4.05 (1H, qd, J=6.3, 4.9), 4.31 (1H, m), and 7.67 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH2:9])=[CH:6][CH:7]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(Cl)nn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(Cl)nn1
Yield: 62 %

Procedure:
A mixture of 3-chloro-6-vinyl-pyridazine (1 g, 7.09 mmol), palladium on carbon (10% wt, 200 mg) in ethyl acetate (14 mL) under a hydrogen atmosphere was stirred vigorously at ambient temperature for 4 hours. The mixture was then filtered through a pad of celite and the filtrate concentrated onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 90:10-50:50) to return 3-chloro-6-ethyl-pyridazine as a white solid (627 mg, 63% yield). 1H NMR (CDCl3) δ 1.27 (3H, t), 2.93 (2H, q), 7.72 (1H, d), 7.83 (1H, d). MS m/z=143 (M+H+)+.