Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].S(OC)(O[CH3:35])(=O)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>CN(C=O)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3](=[N:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[S:4][CH3:35]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(OCCCCN2CCC(N(C)C(=S)Nc3ccccc3)CC2)cc1C
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: CSC(=Nc1ccccc1)N(C)C1CCN(CCCCOc2ccc(C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (2.35 mmol) of the preceding thiourea (10.2) in 10 ml of DMF is treated at 25° C. with 245 μl of dimethyl sulfate, stirred overnight at 25° C. and then heated for 1 h at 60° C. The mixture is evaporated to dryness and the residue is recovered in the usual way and purified by flash chromatography to give 325 mg (Yd: 32%) of a light yellow oil. This oil is taken up in ethanol and salified with a solution of 80 mg of fumaric acid in the same solvent to give 340 mg (Yd: 26%) of compound of formula:
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:2]
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 578.2 g of 4-carboxy-1-ethoxycarbonylpiperidine in 1200 ml of toluene is treated firstly with 1.0 g of N,N-dimethylformamide and then, at from 68° to 70° C. and within the space of 2 hours, with 369.0 g of thionyl chloride. The mixture is subsequently stirred at 70° C. for a further 30 min, after which the toluene is distilled off in vacuo and the residue is then degassed at RT for approximately 30 min under HV. This results in the title compound in the form of a weakly yellow oil [IR (Film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1 ]. The product distils without decomposition at a m.p. of 96°-98° C. (0.08-0.09 Torr).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][CH:16]1[CH2:21][NH:20][C@H:19]([C:22]#[N:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][C@H:16]1[CH2:21][NH:20][C@H:19]([C:22]#[N:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@@H]1CCC(NOCc2ccccc2)CN1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: N#C[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 35 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A suspension of (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine ethanedioate (1:1) (XI) (13 gm, 0.0404 moles) in methanol (260 ml) was heated under reflux, with stirring, for 3 hour. The resulted suspension was allowed to cool to 35° C. and the resulting suspension filtered under suction. The solid was washed with additional methanol (2×13 ml). The solid was dried under reduced pressure (4 mm Hg), to obtain (2S,5R)-5-[(benzyloxy)amino]-2-cyanopiperidine ethanedioate (XIA) as a white solid, 7.3 gm, yield 56%.
Reaction SMILES: [CH2:1]([N:8]([CH3:41])[C:9](=[O:40])[CH2:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([S:17]CC2C=CC(OC)=CC=2)[CH2:14][N:13]1[S:27]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([N:8]([CH3:41])[C:9](=[O:40])[CH2:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([SH:17])[CH2:14][N:13]1[S:27]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)N(C)Cc3ccccc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)CC[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To 131 mg (0.23 mmol) (2R,4R)-N-Benzyl-3-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-N-methyl-propionamide in 8 ml TFA were added 0.37 ml (2.3 mmol, 10 eq) triethyl silane at 0° C. and the solution was stirred for 60 min at 80° C., evaporated, twice suspended in toluene and evaporated. The crude product was purified with prep. HPLC using a RPC18 column yielding 17 mg (2R,4R)-N-Benzyl-3-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-N-methyl-propionamide as light yellow gum, MS: 469 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9](C)[CH:10]=O)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][CH3:10]
Reactant: CN(C=O)c1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1ccc(F)c(Cl)c1
Temperature: 10 °C

Procedure:
A mixture of 42.2 g of 5A and 50 g of concentrated sulfuric acid in 600 ml of water was refluxed for 7 hours. The resulting mixture was charcoaled, filtered, cooled to 10° C. and made alkaline with sodium hydroxide. The resulting mixture was extracted with ether. The extract was dried and the ether evaporated to give 3-chloro-4-fluoro-N-methyl-aniline, (5B), as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:14]>>[CH3:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH:1]=[O:14])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(C)nc2c1
Reactant: O=[Se]=O
Product: Cc1ccc2ccc(C=O)nc2c1
Yield: 71 %

Procedure:
The title compound was prepared from 2,7-dimethylquinoline (6f) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 71% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC.CCOC(C)=O.[F-].[K+]>C1(C)C=CC=CC=1.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>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[S:28][CH:27]=[N:26][CH:25]=3)[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cncs2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A solution of Example A4 (0.35 g, 1.318 mmol) in toluene (8 mL) was sparged with Ar, treated with 5-(tributylstannyl)thiazole (0.493 g, 1.318 mmol) and Pd(PPh3)4 (0.152 g, 0.132 mmol), heated at 110° C. for 16 h, then cooled to RT. The mixture was treated with EtOAc and 10% aq. KF solution, stirred for 1 h and the solids were removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (270 mg, 65%) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.06 (dd, J=5.7, 2.4 Hz, 1H), 2.51 (s, 3H); MS (ESI) m/z: 315.1 (M+H+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (135 mg, 0.725 mmol, available from Fluke), 3,6-dichloropyridazine (90 mg, 0.604 mmol, available from Alfa Aesar) and DIPEA (0.137 mL, 0.785 mmol) in Tert-Butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 100° C. for 20 mins then for 30 mins at 150° C. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 10-50% EtOAc in cyclohexane. The appropriate fractions were collected and concentrated to yield the desired product as a white solid, 1,1-dimethylethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate (114.2 mg). LCMS (Method C): Rt=0.85, MH+=299
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].C([O-])([O-])=O.[K+].[K+].P(=O)([O-])O[C:22](CC)(CC)[C:23]#[N:24]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:22]/[C:23]#[N:24])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: CCOc1cc(C=O)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1cc(/C=C/C#N)ccc1OC
Yield: 59.6 %

Procedure:
3-Ethoxy-4-methoxybenzaldehyde (4.5 g, 25 mmol), K2CO3 (5.2 g, 37.5 mmol), and diethylcyanomethyl phosphonate (4.2 mL, 26.3 mmol) were combined in ethanol (75 mL). The mixture was stirred at reflux for 1.5 h. After all benzaldehyde had been consumed, the reaction mixture was concentrated to about 15 mL, and diluted with CH2Cl2 (150 mL) and H2O (150 mL). The mixture was shaken in a separatory funnel and the layers separated. The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was then titurated from ether to afford >99% of the (E)-3-(3-ethoxy-4-methoxyphenyl)-acrylonitrile 3.03 g as a light tan powder, 60%: 1H NMR (400 M Hz, CDCl3) δ 7.32 (d, 1H, J=16.4 Hz), 7.03 (dd, 1H, J=8.4, 2.0 Hz), 6.94 (d, 1H, J=2.0 Hz), 6.87 (d, 1H, J=8.4 Hz), 6.51 (d, 1H, J=16.8 Hz), 4.11 (q, 2H, J=6.8 Hz), 3.91 (s, 3H), 1.49 (t, 3H, J=6.8 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])([F:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:11]2([F:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=1
Reactant: COc1ccc(Cl)cc1C1(F)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1(F)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-4-fluoro-piperidine 4c (13.8 g, 0.04 mol) in dichloromethane (50 mL) was added 1-chloroethylchloroformate. (7.1 g, 0.05 mol). The mixture was stirred at room temperature for 2 h and then concentrated to dryness. The residual was dissolved in methanol (50 mL) and then heated to reflux for 30 min. The mixture was concentrated to dryness in vacuo, ether was added, the precipitate solid was filtered and washed with ether to obtain 4-(5-chloro-2-methoxyphenyl)-4-fluoropiperidine 4d as its hydrochloride salt. 1H NMR (DMSO-d6): δ 9.10-9.01 (m, 2H), 7.25 (q, J1=8.4 Hz, J2=8.8 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.27 (s, 2H), 3.13-3.04 (m, 2H), 2.79-2.66 (m, 2H), 1.924-1.864 (t. 2H). MS (ESI) m/z (M+H+) 243.98.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NCc2ccc(F)cc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccc(F)cc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 42.6 %

Procedure:
In a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[(4-fluorophenyl)methyl]-6-methyl-3-piperidinecarboxamide (192.5 mg, 0.416 mmol), 5 mL of EtOH, Hunig's base (0.291 ml, 1.665 mmol), and hydrazine anhydrous (0.078 mL, 2.497 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the light yellow title compound (84 mg). LC-MS (ES) m/z=475 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.08-1.24 (m, 3H), 1.58-2.01 (m, 4H), 2.22-2.42 (m, 1H), 2.94 (m, 1H), 4.16-4.42 (m, 2H), 5.38 (s, 2H), 6.08 (s, 2H), 6.55-6.65 (m, 1H), 7.12-7.24 (m, 2H), 7.27-7.39 (m, 2H), 7.58 (dd, J=8.5, 1.1 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 8.50 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:30])[NH:21][CH2:22][CH:23]([CH3:29])[CH2:24][C:25]([F:28])([F:27])[F:26])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:31][CH3:32])[CH:5]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH3:32][O:31][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:30])[NH:21][CH2:22][CH:23]([CH3:29])[CH2:24][C:25]([F:26])([F:27])[F:28])[CH:18]=2)[NH:13][CH:12]=1)[C:3]([OH:33])=[O:2]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
To a solution of 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester (1.80 grams, 3.90 mmol) in 2:2:1 methanol:tetrahydrofuran:water (30 mL) was added lithium hydroxide monohydrate (0.82 grams, 19.50 mmol). The resulting solution was stirred, at room temperature, for 48 hours then concentrated in vacuo. The resulting crude product was treated with 1 M hydrochloric acid (aq), and the resulting precipitate was collected via filtration to vie 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid (1.74 grams, 99% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].[Cl-].[NH4+]>CCCCCC.C1C=CC=CC=1.CCOCC.O>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a reaction vessel equipped with a mechanically driven agitator, water-cooled condenser, addition funnel, thermometer, and nitrogen inlet was added a solution containing 40.0 g. (0.316 mole) of 2-bromopyridine in 400 cc. of anhydrous ether. The solution was cooled to -50° C. using a dry ice-acetone bath. By a dropwise addition, 127 cc. (0.316 mole) of n-butyllithium in n-hexane was added over 25 minutes. The resulting black mixture was stirred for additional 30 minutes. A solution containing 59.8 g. (0.30 mole) of trimethyltin chloride in 200 cc. of anhydrous benzene was added over 40 minutes, followed by a one-hour stirring period. The dark orange solution was warmed to -30° C. over a one-hour period, held at -30° C. for one hour and warmed to room temperature before being hydrolyzed with a saturated aqueous solution of ammonium chloride. The aqueous phase was separated from the organic phase and washed with 200 cc. of ether. The organic portions were combined, dried over a quantity of anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. A dark red liquid (73.9 g.) was isolated and distilled under reduced pressure (0.22 mm). A light yellow liquid fraction boiling at 38°-40° C. was collected and analyzed. The tin content was found to be 47.97%. The calculated tin content for trimethyl-2-pyridyltin is 49.07%. Gas chromatographic analysis indicated a purity of 97% and the nuclear magnetic resonance spectrum contained a singlet at 0 ppm. (CH3 --Sn, 9H's), a complex multiplet centered at 7.0 ppm. (β- and γ-pryidyl H's, 3H's) and a complex doublet at 8.4 ppm. (α-pyridyl H, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([OH:23])=O)=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:56]1([NH2:63])[CH:61]=[CH:60][CH:59]=[C:58]([NH2:62])[CH:57]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[NH2:62][C:58]1[CH:57]=[C:56]([NH:63][C:21]([C:14]2[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[N:16][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)=[N:12][CH:13]=2)=[O:23])[CH:61]=[CH:60][CH:59]=1
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Reactant: Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(N)c1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2, 400 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (970 mg) and 1-hydroxybenzotriazole monohydrate (780 mg), N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (430 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 1,3-phenylenediamine (418 mg) was added at room temperature, and the mixture was stirred at the same temperature for 16 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 95% ethyl acetate/5% methanol) to obtain N-(3-aminophenyl)-2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamide (C6, 272 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].[CH3:12][Mg]Br>CCOCC>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH:10]([OH:11])[CH3:12]
Reactant: C[Mg]Br
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CC(C)O

Procedure:
A mixture of 671.2 g of citral and 185.6 g of diethyl ether is added to an addition funnel. The citral mixture is then added dropwise over a five hour period to a nitrogen blanketed, stirred, 5 L, 3-neck, round bottom flask equipped with a reflux condenser containing 1.6 L of 3.0 M methylmagnesium bromide solution and an additional 740 ml of diethyl ether. The reaction flask is situated in an ice water bath to control exotherm and subsequent ether reflux. After addition is complete, the ice water bath is removed and the reaction allowed to mix for an additional 2 hours at 20-25° C. at which point the reaction mixture is added to 3.5 Kg of cracked ice with good mixing. To this mixture is added 1570 g of 30% sulfuric acid solution. The aqueous acid layer is drained and the remaining ether layer washed twice with 2 L of water. The ether layer is concentrated by evaporation of the ether under vacuum to yield 720.6 g of 4,8-dimethyl-3,7-nonadien-2-ol. To a glass autoclave liner is added 249.8 g of the 4,8-dimethyl-3,7-nonadien-2-ol, 5.8 g or 5% palladium on activated carbon and 200 ml of n-hexane. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged twice with 250 psig N2, once with 250 psig H2 and then charged with 100 psig H2. Upon mixing, the reaction initiates and begins consuming H2 and exotherms to 75° C. The autoclave is heated to 80° C., boosted to 500 psig with H2, mixed for 3 hours and then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of n-hexane under vacuum to yield 242 g of 4,8-dimethyl-2-nonanol.
Reaction SMILES: [CH:1](/[OH:6])=[CH:2]\[CH2:3][C:4]#[CH:5].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:8][CH:7]([O:6][CH2:1]/[CH:2]=[CH:3]/[C:4]#[CH:5])[O:9][CH2:10][CH3:11]
Reactant: C#CC/C=C/O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#C/C=C/COC(C)OCC
Reaction time: 0.33 h

Procedure:
The 2-trans-penten-4-yn-1-ol (47.7 g) was dissolved in ether (50 ml), cooled to 0° and treated with ethyl vinyl ether (50 mL). To this solution, solid p-toluene sulfonic acid (0.1 g) was added and after a slight exothermic reaction, the mixture was stirred for a further 20 min and quenched with triethylamine (2 mL). The solvents were removed in vacuo and the residue was dissolved in ether, washed with aqueous NaHCO3 solution, dried (MgSO4) and concentrated. The residue was purified by liquid chromatography (two columns, 6:1 parts by volume hexane-ethyl acetate) and distilled, bp 88°-98° (26 mmHg) to give (E)-4-methyl-3,5-dioxa-7-decen-9-yne.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncccn2)cc1
Temperature: 90 °C
Yield: 89 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-bromopyrimidine (0.630 g, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and the mixture was purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (240 mg) was then added and the reaction mixture heated to 90° C. for 17 hours. The hot reaction mixture was filtered through celite and concentrated in vacuo to remove the acetonitrile. The resulting aqueous suspension was washed with dichloromethane (2×30 mL) and then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was diluted with water (20 mL), filtered and the solid product dried in vacuo at 50° C. overnight to give the title compound (0.709 g, 89%) as a white solid, m.p. 237° C.