Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]=[C:4](OC)[O:5][CH3:6])#[N:2].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:1]([CH:3]=[C:4]([O:5][CH3:6])[NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:2]
Reactant: NCCSCc1ncccc1Cl
Reactant: COC(=CC#N)OC
Product: COC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
Reaction of 1-cyano-2,2-bis-methoxyethylene (J.A.C.S., 1949, 71, 47) with 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine by the procedure of Example 1(b)(i) yields 1-cyano-2-methoxy-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]-ethylene.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.[PH2:26](=[O:28])[OH:27]>O>[C:1]1([CH:7]([NH:14][C:15]2([PH:26](=[O:27])[OH:28])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC1
Reactant: O=[PH2]O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=[PH](O)C1(NC(c2ccccc2)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Diphenylmethylamine (4.00 ml) and cyclopentanone (2.06 ml) were stirred at 120° C. for 3 hours, and then the mixture was returned to room temperature and added with tetrahydrofuran (2 ml) and phosphinic acid (1.8 g). The mixture was stirred at room temperature for 3 minutes, and then allowed to stand for 17 hours. Water (20 ml) was added to the reaction system, and the insoluble solid was collected by filtration and washed with tetrahydrofuran, and then dried to obtain crude 1-(diphenylmethylamino)cyclopentylphosphinic acid (1.53 g). This compound was subjected to the measurement of molecular weight and then used in the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[C-]#N.[K+].CC[OH:35]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:35])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 80 °C
Yield: 78 %

Procedure:
A steel clabe was charged with a mixture of compound 5 (400 mg, 1.39 mmol), KCN (362 mg, 5.57 mmol) in EtOH (4 mL) and H2O (4 mL). The mixture was heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature and poured into ice (10 g) and filtered. The filter cake was washed with water (10 mL×2) and CH2Cl2 (10 mL×2), dried under reduced pressure to give compound 6 (440 mg, 78%) as a white solid. LC-MS tR=1.219 min in 2 min chromatography, MS (ESI) m/z 333, 335 [M+H]+; 1H NMR (DMSO 400 MHz): δ 10.82 (m, 1H), 8.52 (d, J=27.2 Hz, 1H), 7.53 (m, 1H), 7.34 (m, 2H), 5.78 (d, J=6.4 Hz, 2H), 2.61 (m, 4H), 2.23 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([Br:16])=[C:6]([Cl:15])[C:7]2[O:11][C:10]([F:13])([F:12])[O:9][C:8]=2[CH:14]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[C:5]([Br:16])=[C:6]([Cl:15])[C:7]2[O:11][C:10]([F:13])([F:12])[O:9][C:8]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc2c(c(Cl)c1Br)OC(F)(F)O2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(c(Cl)c1Br)OC(F)(F)O2
Temperature: 90 °C
Yield: 100 %

Procedure:
To the slurry of 6-nitro-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.0 g, 3.16 mmol) in ethanol (4 mL) and water (1 mL) was added ammonium chloride (3.38 g, 63.2 mmol) and iron powder (1.06 g, 18.96 mmol). The mixture was warmed up to 90° C. for 1 h and then cooled down. Filtered through a Celite plug and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% ethyl acetate in hexanes) to afford 6-amino-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole as a white solid (0.90 g, 3.16 mmol, 100%). MS: (ES) m/z calculated for C7H3BrClF2NO2 [M+H]+286.0. found 286.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>>[F:35][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: F[B-](F)(F)F
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)c1
Yield: 46 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (94 mg, 0.208 mmol) and SELECTFLUOR® (73.7 mg, 0.208 mmol) was stirred at 0° C. for 5 h and at RT for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC. The fractions were collected and concentrated. The residue was washed with saturated aq NaHCO3 solution, extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated to give the title compound as yellow solid (45 mg, 46.0%). [M+H] calc'd for C25H32FN5O3, 470. found, 470.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:14])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:14][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(N)cccc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-acetyl-5-amino-1,2,3,4-tetrahydroisoquinoline (6.6 g) in a mixture of dry pyridine (3 g) and dichloromethane (450 ml) at approximately 5° C. was added dropwise, over 15 minutes, benzenesulphonyl chloride (6.2 g). The orange solution was stirred overnight at room temperature and was then washed several times with water, dried and the solvent was then evaporated to give a dark orange oil. Crystallisation from 2-propanol gave 2-acetyl-5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline as a pale pink solid (9.5 g) m.p. 131°-132° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(-c2cccnc2)n(CCCCCCO)c2ccccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(-c2cccnc2)n(CCCCCCCl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)indole (1.37 g) at 0° . The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo yields the crude chloride as an oil. Purification by silica gel chromatography (CH2Cl2 /EtOAc 9.5:0.5) gives 1-(6-chlorohexyl)-3-methyl-2-(3-pyridyl)indole as a light yellow oil; NMR (CDCl3) δ3.30 (t, 2H), 3.92 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:15]3[CH2:16][CH2:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO.O.C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:15]3[CH2:16][CH2:17][NH:18][CH:19]([CH3:20])[C:14]3=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc3n2CCN=C3C)cc1OC
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3n2CCNC3C)cc1OC
Yield: 37 %

Procedure:
6-(3,4-Dimethoxyphenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.3 g) was dissolved in a mixture of 80 ml of methanol and 8 ml of water under argon. The solution was treated portionwise with 0.6 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.3 g of yellow-brown oil, was chromatographed on 60 g of silica gel with methylene chloride/methanol (49:1) as the eluent. The product, 0.9 g of yellow oil was dissolved in a 20-fold amount of ethanol, treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol, concentrated to 10 ml and treated with 40 ml of ethyl acetate. There was obtained 0.5 g (37%) of 6-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:0.6); m.pt.: 172°-175° C. (dec.). A sample was recrystallized from a 40-fold amount of ethanol and yielded the (2:1) fumarate; m.pt.: 178°-180° C. (dec.).
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1)C.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:4]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[O:11])[CH:16]=[CH:17][CH:18]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([NH2:21])[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#CCc1cccc(F)c1
Reactant: CCOC(=O)c1cccnc1
Product: NC(Cc1cccc(F)c1)c1cccnc1
Product: O=C(Cc1cccc(F)c1)c1cccnc1

Procedure:
The title compound was generated from commercially available nicotinic acid ethyl ester and (3-fluoro-phenyl)-acetonitrile according to the general procedure D described above. The intermediates 2-(3-fluoro-phenyl)-1-pyridin-3-yl-ethanone and 2-(3-fluoro-phenyl)-1-pyridin-3-yl-ethylamine were isolated and characterized.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CCOCC.N#N.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3-Bromobenzonitrile (10.0 g, 55 mmol) was dissolved in dry THF (100 mL) and cooled to −100° C. (Et2O/N2). n-Butyllithium (24.2 mL, 2.5 M in hexane) was added over 30 minutes, maintaining the internal temp under −90°. After 20 minutes, triisopropylborate (18.0 mL) was added over 15 minutes, again maintaining the internal temperature. After the addition was complete, the reaction was allowed to warm slowly to room temperature over 1.5 hours. The reaction was stirred at room temp for 16 hours, then cooled to 15° C., after which 6 M HCl (25 mL) was added. After stirring vigorously for 3.5 hours, the reaction was partitioned between water and EtOAc. After extracting a second time with EtOAc, the combined organics were washed with 2 M NaOH. The aqueous extract was neutralized with 6 M HCl. The white precipitate was filtered, yielding the desired product (4.80 g, 60%). 1H NMR (DMSO-d6): δ8.37 (s, 2H), 8.10 (s, 1H), 8.03 (dt, 1H, J=7.3, J′=1.1), 7.83 (dt, 1H, J=7.6, J′=1.4), 7.53 (t, 1H, J=7.7).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O
Yield: 75.8 %

Procedure:
2.0 g (4.51 mmoles) of Z-Glp-Leu-piperidine are dissolved in 40 ml of methanol, 0.4 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is crystallized from ether. 1.12 g (81%) of Glp-Leu-piperidine are obtained; m.p.: 99°-100° C., Rf5 =0.71, [α]D25 =+30.4° (c=1%, in acetic acid). Analysis for amino acids: Glu=0.95 (1.0), Leu=1.00 (1.0).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:38]=[CH:37][C:29]4[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=4[CH:27]=3)[C:22]([OH:24])=O)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:81]1([CH:87]2[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]2)[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]1[NH:30][C:29]2[CH:37]=[CH:38][C:26]([CH2:25][C@@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[C:22](=[O:24])[N:90]3[CH2:91][CH2:92][CH:87]([N:81]4[CH2:86][CH2:85][CH2:84][CH2:83][CH2:82]4)[CH2:88][CH2:89]3)=[CH:27][C:28]=2[N:32]=1
Reactant: O=C(O)[C@@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccc2[nH]c(C(F)(F)F)nc2c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
To a stirred solution of the acid (R)-2-(4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)propanoic acid (33 mg, 0.06 mmol) and diisopropylethylamine (33 mg, 0.25 mmol) in methylene chloride (2 mL) was added a solution of PyBOP (33 mg, 0.06 mmol) and 4-piperidinopiperidine (12 mg, 0.07 mmol) in methylene chloride (1 mL). The reaction mixture was stirred at room temperature for 16 h and was subjected to preparative thin layer chromatography for purification (1:10 2M ammonia in methanol/methylene chloride) to give the title compound (4.6 mg, 12% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.73-7.71 (m, 1H), 7.62 (bs, 1H), 7.39-7.36 (m, 1H), 7.19-7.11 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 5.06-5.02 (m, 1H), 4.67-4.58 (m, 1H), 4.49-4.40 (m, 1H), 4.38 (s, 1H), 4.33 (bs, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.22-3.14 (m, 3H), 3.04-2.87 (m, 4H), 2.79-2.71 (m, 1H), 2.58-2.48 (m, 1H), 2.44-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.04-1.92 (m, 1H), 1.86-1.43 (m, 11H), 1.33-1.29 (m, 1H), 0.94-0.84 (m, 1H), −0.04-−0.12 (m, 1H). LC/MS: tR=1.97 min, 681 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16](I)[C:3]=12.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22]3)=[O:20])[N:15]=[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[C:3]=12
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Yield: 30.6 %

Procedure:
Nitrogen was bubbled through a suspension of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (70 mg, 0.144 mmol), 4-fluorophenylboronic acid (22 mg, 0.158 mmol) and K3PO4 (92 mg, 0.43 mmol) in DMF (1.1 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.014 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and partially purified by preparative HPLC. The residue was purified by chromatography (silica gel, isohexane/ethyl acetate 1:0 to 7:3) to provide Compound 1 (20 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:28])([F:27])[F:26].CI.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:1])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of diisopropylamine (2.97 mL, 20.85 mmol) in THF (22 mL) was stirred at 0° C. and treated dropwise with n-butyllithium (1.6 M in hexane, 13.03 mL, 20.85 mmol). The resulting solution was stirred for 5 min, and then was cooled to about −75° C. Once at the prescribed temperature, a solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate (4.39 g, 17.38 mmol) in THF (44 mL) was added dropwise over a 15 min period. The resulting solution was stirred at about −75° C. for 30 min, and then warmed to 0° C. Once at the prescribed temperature, the solution was rapidly treated with methyl iodide (1.630 mL, 26.1 mmol). The resulting solution was stirred for 30 min, treated with 1.0 M aqueous HCl and then extracted three times with ethyl acetate. The combined organic phases were washed with 5% aqueous sodium bisulfite (2×25 mL) followed by saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 5-15% ethyl acetate-hexane, to provide racemic methyl 2-(4-chloro-3-(trifluoromethyl)-phenyl)propanoate as a colorless oil (3.444 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.0 Hz, 1 H), 7.47 (d, J=8.4 Hz, 1 H), 7.42 (dd, J=8.4, 2.0 Hz, 1 H), 3.76 (q, J=7.3 Hz, 1 H), 3.68 (s, 3 H), 1.52 (d, J=7.3 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([N+:12]([O-])=O)[CH:4]=1.[CH:15]1([NH:18][C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][C:19](=[O:20])[C:21]2[CH:28]=[CH:27][C:24]([C:25]3[NH:12][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Product: COc1ccc2nc(-c3ccc(C(=O)NC4CC4)cc3)[nH]c2c1

Procedure:
Compound 635 was prepared according to the procedure similar to that described in Scheme III from 1-methoxy-3,4-dinitrobenzene and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C18H17N3O2: 308.14; found: 308.16.
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:30][C:31](=[O:34])[CH2:32]C)(=[O:29])[CH2:27][CH3:28].[OH-:35].[NH4+]>>[C:31]([OH:30])(=[O:34])[C:32]([OH:22])=[O:35].[C:1]1([N:7]([C:8]2([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[C:26](=[O:29])[CH2:27][CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCOCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Reactant: CCC(=O)OC(=O)CC
Agent: [NH4+]
Product: CCCOCC1(N(C(=O)CC)c2ccccc2)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 13.1 parts of N-phenyl-1-(phenylmethyl)-4-(propoxymethyl)-4-piperidinamine and 20 parts of propionic acid anhydride is stirred and refluxed for 6 hours. After cooling, the reaction mixture is poured onto ice-water and the whole is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is converted into the ethanedioate salt in 2-propanone and 2-propanol. The salt is filtered off and crystallized from acetonitrile, yielding N-phenyl-N-[1-(phenylmethyl)-4-(propoxymethyl)-4-piperidinyl]propanamide ethanedioate; mp. 180.3° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([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])[CH2:3][CH2:2]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:46]2[CH:50]=[CH:49][NH:48][N:47]=2)[CH:40]=1>C1COCC1>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:46]2[CH:50]=[CH:49][N:48]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)(=[O:8])=[O:9])[CH:11]=3)=[O:15])[N:47]=2)[CH:40]=1
Reactant: Oc1ccc(Cl)cc1-c1cc[nH]n1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(c1cccc(S(=O)(=O)N2CCOCC2)c1)n1ccc(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-(morpholinosulfonyl)benzoic acid (50 mg, 0.184 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (37.4 mg, 0.276 mmol), EDC (53.0 mg, 0.276 mmol) and Sodiumbicarbonate (17.03 mg, 0.203 mmol) was dissolved in THF (10 mL) and then 4-chloro-2-(1H-pyrazol-3-yl)phenol (35.9 mg, 0.184 mmol) was added at room temperature and reaction mixture was allowed to stirred for overnight at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (3-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-1-yl)(3-(morpholinosulfonyl)phenyl)methanone (43 mg, 0.094 mmol, 51.0% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.39 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.53 (d, 1H, J=2.4 Hz), 7.38 (dd, 1H, J=2.4 & 8.4 Hz), 7.27 (d, 1H, J=8.4 Hz), 6.52 (s, 1H), 3.75 (m, 4H), 3.05 (m, 4H). ESI-MS: 448.0 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.