Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:36][O:35][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:19][C@@H:5]34)[CH:10]=2)=[C:29]([C:28]([F:27])([F:40])[F:41])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3(=O)=O
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)S(=O)(=O)CCN4[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]32)c(C(F)(F)F)c1
Yield: 74.2 %

Procedure:
The bromo-indoline (0.6 mmol), boronic acid (0.8 mmol) and barium hydroxide (1 mmol) were stirred into a solution of water (4 mL) and DME (8 mL), then heated at 60° C. while bubbling through a stream of Argon gas for 20 min. The reaction mixture was then cooled to room temperature and Pd(PPh3)2Cl2 (0.03 mmol) and PPh3 (0.09 mmol) were quickly added and refluxing resumed for 4 hours. When the reaction was completed as shown by TLC, ethyl acetate (10 mL) was added and the mixture was filtered through a Celite bed. Organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. This residue was purified on a flash column eluting with 10% EtOAc/Hexanes to give the desired product in 60-95% yield. tert-butyl(6bR,10aS)-5-[4-methoxy-2-(trifluoromethyl)phenyl]-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (135 mg, 74%) was prepared via coupling of the tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (150 mg, 0.338 mmol) with 2-trifluoromethyl-4-methoxyphenyl boronic acid (112 mg, 0.507 mmol) using the general procedure described above.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a suspension of 4-{(R)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was purified by preparative TLC using dichloromethane/MeOH (15:1) as mobile phase (twice) followed by a column chromatography on silica gel using dichloromethane/MeOH (15:1) as eluent to give the desired product (12 mg, 5%); LCMS (UV, ESI), m/z 493 (M); HPLC: 99%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O.[Cl-].[Na+].O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(NS(=O)(=O)c2ccc(CBr)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(S(=O)(=O)Nc3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
Add 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2.77 g, 14.2 mmol) to sodium hydride (396 mg, 15.7 mmol) in dimethylformamide (20 mL) at 0° C., stir 10 minutes, add 4-bromomethyl-N-(3-cyano-phenyl)-benzenesulfonamide (2.50 g, 7.12 mmol) in dimethylformamide (15 mL) drop wise via addition funnel. After 2 hours at ambient temperature, pour into brine (40 mL), extract with ethyl acetate (2×40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify residue by flash chromatography to yield the title compound (1.17 g, 2.52 mmol): MS (m/z): 463 (M−1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:12]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C#CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of but-3-ynyl 4-methylbenzenesulfonate (972 mg) and N-methyl piperazine (482 μL) was heated to 80 C for 4.5 h, diluted with 1,2-dichloroethane (5 mL) and heated to 70° C. for 18 h. Saturated aq. NaHCO3 was added (10 mL) and the mixture was extracted with DCM (3×40 mL), and concentrated to afford 0.70 g of 1-(but-3-ynyl)-4-methylpiperazine as a 3:2 mixture of tosylate salt and free base.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]([CH:13]([CH3:15])[CH3:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1>>[CH2:2]([O:9][C:10](=[O:16])[C@H:11]([CH:13]([CH2:14][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:23][CH:24]=1)[CH3:15])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Product: CC(CCc1ccc(-c2ccccc2C#N)cc1)[C@H](N)C(=O)OCc1ccccc1

Procedure:
L-valine benzyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1>ClCCl>[Br:21][C:20]([Br:24])=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A flask was charged with triphenylphosphine (477 g, 1.82 mol) and dichloromethane (2,500 ml) was cooled to 0° C. A solution of carbon tetrabromide (302 g, 910 mmol) in dichloromethane (300 ml) was added dropwise, followed by the dropwise addition of a solution of tert-butyl 3-(2-oxoethyl)pyrrolidine-1-carboxylate (97 g, 455.40 mmol, 1.00 equiv) in dichloromethane (200 ml). The resulting solution was allowed stir for 1.5 hours at 0° C. The reaction mixture was washed with 4,000 ml of petroleum ether, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl 3-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH:20]1[C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=[C:21]1[NH2:22]>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:22]1[C:21]1[NH:20][C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Solvent: CO
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2nc3nc[nH]c3c(=O)[nH]2)C1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.5 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (1.33 g) was dissolved in a mixture of methanol (300 ml) and water (300 ml). To the solution was added guanine (0.76 g). The mixture was stirred at ambient temperature for three days and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-hypoxanthinyl)morpholin-2-yl]hypoxanthine (2.20 g).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24])(=[O:19])(=[O:18])[NH2:17]>COCCOC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([S:16](=[O:18])(=[O:19])[NH2:17])[CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reaction time: 144 h
Yield: 44.8 %

Procedure:
In a 1 liter round bottom flask were placed phenyl hydrazine (54.1 g, 0.5 mol), triethylamine (50.5 g, 0.5 mol), and 150 ml of 1,2 dimethoxyethane. Then the mixture was cooled to ice-bath temperature and with good stirring and over 10 minutes a solution of 3-sulfamoyl-4-chlorobenzoyl chloride 97.1% (61 g, 0.24 mol) in 150 ml 1,2 dimethoxyethane was added dropwise. The reaction was permitted to reach ambient temperature. After standing for 6 days the solvent was evaporated under vacuum and the residue taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 2N H2SO4, with water and finally with 1 molar sodium bicarbonate solution. The ethyl acetate phase was separated and dried with magnesium sulfate, clarified and concentrated to crystallization. 35 g of product mp 189°-190° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[N:16]1[CH2:25][C:26](O)=[O:27]>>[C:7]([C:4]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:26](=[O:27])[CH2:25][N:16]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][CH:18]=3)[CH2:23][CH2:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: N#Cc1csc(N)c1-c1nccs1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: N#Cc1csc(NC(=O)CN2C(=O)CCc3ncccc32)c1-c1nccs1
Yield: 4.3 %

Procedure:
The title compound was prepared from 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (67 mg, 0.32 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (100 mg, 0.48 mmol) according to protocol A. The crude product was purified by column chromatography (2% methanol/methylene chloride) and HPLC to give N-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (5.4 mg) as a white solid. LCMS m/z 396.1, method [7] retention time 2.611 min. 1H-NMR (300 MHz, CDCl3) δ 8.39 (d, J=4.1 Hz, 1H), 7.76 (d, J=3.3 Hz, 2H), 7.62 (s, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.44 (m, 2H), 3.46 (t, J=7.1 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 1-(2-chloroethyl)piperidine hydrochloride(421 mg, 2.29 mmol) and potassium carbonate(862 mg, 6.24 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow brown solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to give a yellow viscous oil (560 mg, 88.7%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06-8.05 (m, 1H), 7.24 (d, J=9.0 Hz, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.02-2.95 (m, 2H), 2.73-2.67 (m, 2H), 2.57-2.48 (m, 6H), 1.59-1.44 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[C:11]2[S:15][C:14](=[S:16])[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]2=[O:21])[C:8]([OH:10])=[O:9])[N:6]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C>[C:8]([C:7](=[C:11]1[S:15][C:14](=[S:16])[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]1=[O:21])[C:5]1[N:6]=[C:2]([NH:1][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[S:3][CH:4]=1)([OH:10])=[O:9]
Reactant: Nc1nc(C(C(=O)O)=C2SC(=S)N(CC(=O)O)C2=O)cs1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)CN1C(=O)C(=C(C(=O)O)c2csc(NC(=O)Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 1 g of 5-[1-(2-aminothiazol-4-yl)-1-carboxymethylene]rhodanine-3-acetic acid, 3.9 g of phenyl isocyanate and 10 ml of hexamethylphosphoric triamide. The resulting product was a ellow powder having the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.N1C=CC([NH:13][C:14](N)=[S:15])=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:14]([NH2:13])=[S:15])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: NC(=S)Nc1cc[nH]n1
Product: Cn1ccc(NC(N)=S)n1

Procedure:
This material is prepared from 1-methyl-1H-pyrazol-3-ylamine following the procedure described for the preparation of (1H-pyrazol-3-yl)-thiourea (35a)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[C:31]([C:35]1[O:36][C:37]([CH2:40]Cl)=[N:38][N:39]=1)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:31]([C:35]1[O:36][C:37]([CH2:40][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:38][N:39]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CC(C)(C)c1nnc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nnc(C(C)(C)C)o3)c2=O)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (2.565 g, compound B50) and 2-tert-butyl-5-(chloromethyl)-1,3,4-oxadiazole (1050 mg, compound D29) in dry DMF (50 ml) is added potassium carbonate (829 mg). The mixture is stirred for 3 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo to afford the title compound as a solid
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21].O>O1CCOCC1>[CH2:18]([NH:19][C:20](=[O:21])[O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[CH2:17][CH2:16][CH3:15]
Reactant: CCCCN=C=O
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: C1COCCO1
Solvent: O
Product: CCCCNC(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 92.4 %

Procedure:
1-(Phenylmethyl)piperidin-4-ol (10 g, 52.2 mmol) was stirred in dioxane (90 ml) at room temperature. N-butyl isocyanate (5.0 g, 52.2 mmol) in dioxane (10 ml) was added and the reaction mixture was heated under reflux for 24 h. Water (20 ml) was added and the reaction mixture was concentrated in vacuo to give a brown oil. The crude product was partitioned between diethyl ether and water and the organic extracts were dried (MgSO4) to give the title compound as an oil (14 g, 92%).
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:29][NH:30][CH3:31].CN(C=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[C:9]([CH2:10][N:30]([CH3:31])[CH3:29])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(C)(C)C
Reaction time: 1 h

Procedure:
2-[2-(3-Tert-butyl-4-formylpyrazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.13 mmol) and dimethylamine hydrochloride (20 mg, 0.23 mmol) were mixed with DMF (0.3 mL) and acetic acid (0.3 mL). Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with MeOH and water and directly purified by preparative reverse phase HPLC. The clean product was passed down an SCX cartridge and the volatiles were blown off under a nitrogen atmosphere (2.1 mg, 5 μmol, 4%).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[NH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:13]=2)[CH2:10][CH2:11]1
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: c1ccc(Cn2cc(C3CCNCC3)c3cccnc32)nc1

Procedure:
This compound was prepared following the procedure described in example 24, parts C and D, starting with 0.2 g (0.66 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.149 g (0.86 mmol) of 2-bromomethylpyridine. After standard work-up, 0.21 g (72% of yield) of the expected product were isolated.
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-:22].OO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]([NH2:10])=[O:22])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CCO
Product: COc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 89.7, 0.15 g, 0.53 mmol) in EtOH (10 mL) was added NH4OH (0.18 mL, 2.66 mmol, 14.8 M in H2O), followed by H2O2 (1.8 mL, 26.6 mmol, 50% in H2O). The mixture was stirred at room temperature overnight, then cooled to 0° C. and carefully quenched with 1 M Na2S2O3 solution (26 mL). The mixture was extracted with EtOAc (×2) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (5% MeOH in CH2Cl2) to yield 0.1 g (63%) of the title compound as a white solid. m/z (ES+) 287(M+H)+. 1H NMR (400 MHz, Methanol-d4) δ7.50 (s, 1H), 7.33 (s, 1H), 4.03 (s, 3H), 3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m, 2H), 2.11-1.88 (m, 3H), 1.83-1.71 (m, 1H).
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Li+:23].P([O-])([O-:27])([S-])=S.[S]>>[OH:27][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:23]
Reactant: [O-]P([O-])(=S)[S-]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Agent: [S]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]
Temperature: 74 °C

Procedure:
A lithium hydroxystearate grease thickener ws prepared by saponification of a mixture containing 12-hydroxystearic acid (8%) and glyceride thereof (9%) with lithium hydroxide in a mineral oil vehicle at about 174° C. in a closed contactor. After depressuring and dehydration of the thickener in an open kettle sufficient mineral oil was added to reduce the thickener content to about 9.0%. After cooling to about 74° C. a typical grease additive package, consisting of an amine antioxidant, phenolic antioxidant, metallic dithiophosphate, sulfur-containing metal deactivator and nitrogen containing antirust additives, was added.
Reaction SMILES: [NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:29]=[C:28]3[C:23]([CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27]3)=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:29]=[C:28]2[C:23]([CH2:24][NH:25][CH2:26][CH2:27]2)=[N:22]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CNCC2
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-(3-(4-amino-3,4-dioxo-1-phenylbutan-2-ylcarbamoyl)pyridin-2-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate in dioxane (5 ml) 400 μL of 4M HCl in dioxane were added and stirred over night at room temperature. The mixture then was concentrated, and the remainder purified by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) to give 24 mg of the title compound; ESI-MS [M+H]+: 419.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1ccccc1-c1cncc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccccc5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-phenyl)-pyridine.