Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[CH2:13]=[O:14].CO>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:13][OH:14])=[C:7]2[OH:12]
Reactant: C=O
Reactant: Oc1ccnc2c(Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cnc2c(Cl)cccc2c1O

Procedure:
8-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 8-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p. >300° (from methanol).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[F:17][C:2]([F:1])([F:16])[C:3]([O:11][Si:12]([CH3:14])([CH3:15])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)(F)F
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)(F)F

Procedure:
A stirred mixture of 6.66 g of 4-trifluoromethyl-4-trimethylsiloxy-1-octyne and 26 mg. of azabisisobutyronitrile, under argon, is treated with 6.95 ml. of tri-n-butyl tin hydride, via a syringe. After treatment, a condenser is attached to the reaction vessel and the reaction mixture, under argon, is slowly heated to 130°-135° C. and maintained at that temperature for 1.5 hours. Subsequent fractional distillation of the reaction mixture at approximately 0.07 mm pressure gives the desired product, b.p. 125°-135° C. (containing a minor amount of the corresponding cis isomer).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[OH-].[NH4+:14]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:14])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: [NH4+]
Reactant: Cn1cc(Br)c2c(Cl)ncnc21
Agent: [OH-]
Product: Cn1cc(Br)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A suspension of 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (17 g, 69.0 mmol) in ammonium hydroxide (150 mL, 3852 mmol) was stirred for 2 days at 100° C. in a sealed vessel. The reaction was allowed to cool to room temperature and filtered. The collected solid was washed with Et2O to afford the product 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12.5 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCI
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5g, 0.127 moles) and 1-iodohexane (3.75 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours. The mixture is diluted with ether (300 mL) and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil. (Mass spectrometry also revealed a small amount of diethyl 1,3-dihexyl-2,5-dioxo-4-imidazolylphosphonate) MS (EI) 321
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5]C1C=C2C(C=CN2)=CC=1)[CH3:2].C(O[C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([NH2:31])=[O:30])[CH:24]=[C:23]2[N:32]=[C:33]=[O:34])C=C>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:28]1[CH:27]=[C:26]2[C:22]([C:23]([N:32]=[C:33]=[O:34])=[CH:24][N:25]2[C:29](=[O:30])[NH2:31])=[CH:21][CH:20]=1)[CH3:2]
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: CCOC(=O)Cc1ccc2cc[nH]c2c1
Product: CCOC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid ethyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of methyl 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoate (250 mg, 0.59 mmol) and sodium hydroxide (23 mg, 0.59 mmol) in tetrahydrofuran and water (1:1) was stirred at room temperature for about 1 hour. Tetrahydrofuran was removed in vaccuo and aqueous layer was diluted with water (5 mL) and acidified with hydrochloric acid (2N, upto pH 2). The solid thus obtained was filtered and dried to afford 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (170 mg, 70%). The material was taken as such for the next step.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[CH2:10](Br)[C:11]#[CH:12].C(OCC)(=O)C>C1COCC1>[CH2:12]([O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: OCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCOCCOCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (23 mmol) in dry THF (20 mL) at 0° C. under nitrogen was added a THF solution (100 mL) of diethylene glycol (110 mmol) over 0.5 h. The resultant reaction mixture was allowed to stir at room temperature for 1 h. This was followed by the addition of propargyl bromide (21 mmol). The reaction mixture was then heated under reflux for 8 h. Following this, the reaction was cooled, concentrated in vacuo and diluted with water (30 mL). The mixture was then extracted with ethyl acetate (3×50 mL). The organics were combined, dried over sodium sulfate and the concentrated under vacuum to furnish a crude residue. This was subjected to column chromatography using hexanes and ethyl acetate to afford 22 as a clear oil. Yield 2.1 g (71%).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:12][C:10](=[O:11])[C:6](=[C:7]([CH3:9])[CH3:8])[CH2:5][CH2:4]1.[OH-:13].[K+]>>[C:10]([OH:11])(=[O:13])[CH2:12][C@@H:3]([CH2:4][CH2:5][CH:6]=[C:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Agent: Cl
Agent: [K+]
Product: CC(C)=CCC[C@@H](C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44.3 g of HCl gas (measured by determining the weight gain) were passed into 187.2 g (1.045 mol) of technical (85% pure) (R)-pulegone (or R-(+)-p-menth-4(8)-en-3-one) while cooling in ice. After the reaction solution had stood overnight, it was poured into 2.0 l of 5% strength KOH solution and stirred at RT (=room temperature) for 2 h. It was subsequently extracted 5 times with 200 ml of diethyl ether each time. The extract contains pulegone and isopulegone, which can be reused. On addition of concentrated HCl to the aqueous phase (to pH=2), the citronellic acid separated out as a yellowish oil. The acid was extracted by shaking 5 times with 200 ml of diethyl ether each time, the organic phase was dried with Na2SO4 and, after the solvent had been stripped off, was distilled under reduced pressure (boiling point 105°-110° C. under 0.04 mbar). 84.6 g (0.486 mol=45.5% of theory) and, on reuse of the extracted ketones under similar conditions conditions [sic], a further 44.4 g (0.255 mol) of (R)-(+)-citronellic acid were obtained as a clear liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To a mixture of ethyl (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (134 mg), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (0.51 mL). The whole was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was acidified by 1M hydrochloric acid, and then extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (57 mg, 43%) as a yellow amorphous solid. MS 519 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
In 200 ml of acetonitrile were dissolved 33.6 g (0.39 mole) of piperazine and 10.0 g (0.065 mole) of 2-chlorobenzoxazole, and 9.0 g (0.065 mole) of potassium carbonate and a catalytic amount of potassium iodide were added thereto. The mixture was refluxed by heating for 11 hours under stirring. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9:1) to obtain 7.54 g of 1-(2-benzoxazolyl)piperazine as white crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36]([C:30]5([O:29][CH3:28])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC1(C(=O)O)CCCCC1
Agent: Cl
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CCCCC1

Procedure:
The title compound, white solid (17.4 mg, 40.8%), MS (ISP) m/z=472.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 1-Methoxycyclohexane-1-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:10])[CH3:11])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1cccc(-c2ccc(F)cc2F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 100.3 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (6.00 g), 2,4-difluorophenylboronic acid (2.82 g), 2M aqueous sodium carbonate solution (45 ml) and tetrakis(triphenylphosphine)palladium(0) (647 mg), the yellow amorphous title compound (6.39 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:20]O)[CH:8]=2)[NH:3]1.[Se](=O)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1
Reactant: O=C1Nc2ccc(-c3cccc(C=NO)c3)cc2C12CCCCC2
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A solution of 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10 cm3) was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the mixture was concentrated and the residue purified by column chromatography (SiO2, EtOAc: hexane 1:4) and the product re-crystallized from EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%) as a white solid: m.p. 190-191° C.; 1H NMR (CDCl3) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54 (t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7.2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[CH:12]1([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([NH:23][C:21]([CH:18]4[CH2:20][CH2:19]4)=[O:22])[N:3]=[CH:4]3)=[CH:9][N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1cc2cnc(C3CCCCC3)cc2cn1
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2cnc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of 3-chloro-7-cyclohexyl-2,6-naphthyridine (80.0 mg, 0.324 mmol), cyclopropanecarboxamide (47.7 mg, 0.560 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (6.0 mg, 0.011 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2-4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (9.2 mg, 0.012 mmol), and cesium carbonate (240.1 mg, 0.7369 mmol) in 1,4-dioxane (2 mL, 20 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted in ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 63.2 mg (66%) of N-(7-cyclohexyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.090, M+H=296.1, method=E; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.28 (s, 1H), 9.19 (s, 1H), 8.55 (s, 1H), 7.72 (s, 1H), 2.89-2.73 (m, 1H), 2.14-2.03 (m, 1H), 1.96 (d, J=11.6 Hz, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.74 (d, J=12.6 Hz, 1H), 1.63-1.51 (m, 2H), 1.43 (dd, J=25.4, 12.6 Hz, 2H), 1.34-1.18 (m, 1H), 0.85 (dd, J=8.3, 6.5 Hz, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Reactant: Cc1cccc(N2CCNCC2)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(c3ccc(S(C)(=O)=O)nn3)CC2)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylsulfonyl)pyridazine, 3 parts of 1-(3-methylphenyl)piperazine, 2 parts of N,N-diethylethanamine and 180 parts of benzene was stirred for 24 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off and dried, yielding 5 parts (89%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-(methylsulfonyl)pyridazine; mp. 201° C. (compound 209).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17]([C@H:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:33])[CH3:32])[CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[OH:8][CH:9]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17]([C@H:19]([NH:29][C:30](=[O:35])[C:31]([NH2:34])([CH3:33])[CH3:32])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(O)c1ccccc12
Reaction time: 1 h

Procedure:
To a solution of 74 mg of N-[1(R)-[(2,3-Dihydro-3-oxo-spiro[1H-indene-1,4'-piperdin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methylpropanamide trifluoroactate (prepared as described in Example 74) in 10 mL of methanol 0° C. was added 37 mg of sodium borohydride and stirred for 1 h. The reaction was poured into 5 mL of saturated aqueous sodium bicarbonate solution and extracted with chloroform (3×10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous potassium carbonate, filtered, and concentrated to give a colorless foam.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11].[N+](=[CH2:27])=[N-].C(O)(=O)C>C(OCC)C>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([O:16][CH3:27])=[O:15])=[O:11]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccc(C)cc1
Temperature: 0 °C

Procedure:
To a suspension of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid (100 mg) in diethyl ether (10 ml) was added a solution of diazomethane in diethyl ether (10 ml) with stirring at 0° C. After the mixture was stirred at room temperature for 1 hour, excess diazomethane was decomposed with acetic acid. The reaction mixture was washed successively with saturated sodium bicarbonate solution and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 60 mg of methyl 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionate as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:23](=[O:25])[C:22]2[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([S:17]([CH3:16])(=[O:18])=[O:19])[CH:21]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cccnc1Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1Cl

Procedure:
The title compound was prepared in analogy to example 90, from 2-chloro-N-methyl-3,4′-bipyridin-3′-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (12%). MS (ESI): m/z=470.055 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16](O)=[O:17])[C@H:13]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:12]1)(=[O:10])=[O:9].[CH2:28]1[C:30]([NH2:33])([C:31]#[N:32])[CH2:29]1.Cl>>[C:31]([C:30]1([NH:33][C:16]([C@@H:14]2[CH2:15][CH:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]2[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:17])[CH2:28][CH2:29]1)#[N:32]
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Reactant: N#CC1(N)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2CC(S(=O)(=O)c3ccccc3Cl)C[C@H]2COc2ccc(Cl)cc2)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture) and 1-amino-cyclopropyl cyanic hydrochloride to afford the desired product as a yellow oil. MS (EI): 493.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH:22](=[O:24])[CH3:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:22]([OH:24])[CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg) in THF (20 mL) at −78° C. was added n-butyllithium (0.94 mL of a 2.5 M solution in hexanes) and the reaction stirred at −78° C. for 1 h. Then, acetaldehyde (0.33 mL) was added and the reaction allowed to warm to room temperature over 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were dried (MgSO4) and reduced in vacuo to give 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol as a cream solid.