Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][N:26]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: Clc1cc(Cl)cc(-c2ccc3c(c2)CCNC3)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4cc(Cl)cc(Cl)c4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
A suspension of 1.85 g (0.0095 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 105 ml of dimethylformamide was treated with 250 g (0.00795 mol) of 6-(3,5-dichlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.66 ml (0.026 mol) of triethylamine and stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 30 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent. Crystallization was then carried out, firstly from methanol/ethyl acetate/n-hexane and then from hot ethyl acetate. 1.21 g (38%) of 5-[6-(3,5-dichlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as white crystals; m.p. 205°-211°.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCc1ccncc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.96 ml), and then diphenylphosphinic chloride(1.33 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.94 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1), thereby yielding 2.26 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH2:31]C1C=CC(C(OC)=O)=C(C)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:28]([CH3:31])[CH:29]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)cc1C
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1C

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-2-methylbenzoate: 1H-NMR (CDCl3) δ 8.38 (1H, dd, J=8.1, 3.1 Hz), 8.30–8.24 (1H, m), 8.05 (1H, d, J=3.1 Hz), 7.88 (1H, d, J=8.1 Hz), 7.26–7.08 (6H, m), 4.71 (2H, d, J=5.9 Hz), 3.90 (3H, s), 3.87 (3H, s); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](O)([C:8](F)(F)F)=O>C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:3][C:2]1[NH:1][CH:5]=[CH:6][CH:8]=1
Reactant: c1cc[nH]c1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Reaction time: 0.5 h
Yield: 381.1 %

Procedure:
To a solution of p-formaldehyde (1100 mg, 35 mmol) in pyrrole (50 ml, 720 mmol), at 50° C., TFA (416 mg, 3.5 mmol) was added. The reaction mixture was kept under magnetic stirring, at room temperature, for 30 minutes, then ethyl acetate was added and the solution washed with NaHCO3 saturated solution, then the organic phase was dried on Na2SO4. After evaporation the crude product was purified by chromatography on silica gel (Petroleum Ether/Ethyl acetate 4/1+1% TEA). 1950 mg (yield 38%) of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O.C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1C(=O)Cl

Procedure:
In one embodiment, the step comprises combining 2-chloro-6-methylbenzoic acid with, e.g., thionyl chloride or oxalyl chloride, optionally in the presence of a catalytic amount of DMF, to afford 2-chloro-6-methylbenzoyl chloride.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)(=O)=O>CN(C=O)C>[CH2:3]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:27]4[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
2A (0.77 g, 3.75 mmol) was dissolved in dry DMF (20 mL) and Cs2CO3 (2.44 g, 7.50 mmol) was added. The reaction mixture was stirred at room temperature for 10 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.88 g, 7.50 mmol) was added. The reaction mixture was thereafter stirred at 90° C. for 24 h. The mixture was filtered and the solvent was evaporated. The residue was dissolved in DMSO (6 mL) and purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated. There was obtained 1.00 g (74%) of 3A as an oil which solidified on standing at room temperature. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.34 (s, 4H), 3.46 (s, 2H), 3.99 (dd, 2H), 4.28 (dd, 2H), 4.73 (s, 4H), 4.84 (m, 1H), 6.68 (d, 2H), 7.15 (d, 2H), MS (APCI+) m/z 361 [M+H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[OH:22][C:23]1C=CC(C#N)=C(OC)C=1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: COc1cc(O)ccc1C#N
Product: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (2.46 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methoxy-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.62 min, [M+H]+=296.97.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:20][CH3:21])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(O)cccc2n1CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(OCC)cccc2n1CC
Temperature: 120 °C
Yield: 99.7 %

Procedure:
A mixture of 1-ethyl-4-hydroxy-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.43 mmol) and NaH (13 mg, 0.52 mmol) was stirred in DMF (3 mL) for 10 min. Ethyl iodide (80 mg, 0.52 mmol) diluted in 1 mL of DMF was added and placed in a sealed tube. The reaction mixture was heated to 120° C. via microwave for a period of 15 min. The reaction mixture was taken up in 100 mL of EtOAc and washed with 100 mL of 0.1N hydrochloric acid, brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed to produce 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (112 mg, 100% yield) as brown oil. This material was diluted in 2 mL of methanol and 2 mL of 1N NaOH and placed in a sealed tube. The reaction mixture was heated to 120° C. via microwave for 15 min. The reaction mixture was diluted in 100 mL of EtOAc and washed with 50 mL of 1N HCl, 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed to afford 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (100 mg, 100% yield) as a white solid. LCMS for C13H15NO3 calcd. (m/e) 233, observed 234 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[C:11]1([C@@H:17]2[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:9]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][C@H:20]2[CH2:19][CH2:18][C@@H:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)[C:7]=1[I:8])[CH3:10]
Reactant: CCc1ncnc(Cl)c1I
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1I

Procedure:
Prepared as in Example 1 from 4-chloro-5-iodo-6-ethylpyrimidine and cis-4-phenylcyclohexylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]([O:22][CH3:23])[C:20]#[CH:21])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH:19]([O:22][CH3:23])[C:17]2[CH:16]=[C:15]([O:24][CH3:25])[C:14]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(C(C#Cc2c(C)nc(N)nc2N)OC)cc(OC)c1OC
Yield: 93.5 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a yellow powder (335 mg, 93%): Rf=0.29 (9:1, CHCl3:MeOH); mp=127-129° C.; 1H NMR (DMSO-d6) δ 6.84 (s, 2H), 6.37 (s, 2H), 5.34 (s, 1H), 3.78 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO-d6) δ 167.6, 164.3, 161.1, 152.8, 137.2, 134.8, 104.6, 95.7, 87.5, 81.8, 73.1, 60.0, 55.8, 55.3, 22.4; HRFAB[M+Li]359.1701 (calculated C18H22N4O4Li: 359.1719). (R)-4-Isopropyl-3-(2-(3,4,5-trimethoxyphenyl)acetyl)oxazolidin-2-one. To a flame-dried 100 mL round-bottom flask was added 3,4,5-trimethoxyphenylacetic acid (2.10 g, 9.29 mmol). THF (25 mL) was added followed by Et3N (1.42 mL, 10.22 mmol). The solution was cooled to −78° C. Pivaloyl chloride (1.26 mL, 10.22 mmol) was added dropwise and the solution warmed to 0° C. and stirred for 1 h. In a separate flame-dried 50 mL round-bottom flask was added (R)-4-isopropyloxazolidin-2-one (1.0 g). THF (20 mL) was added and the solution cooled to −78° C. n-BuLi (6.83 mL, 9.29 mmol, 1.36 M) was added dropwise and the solution stirred at −78° C. for 15 min and then warmed to 25° C. where it was stirred for 15 min. The organolithium solution was transferred to the solution of the mixed anhydride via cannula at −78° C. The reaction was stirred at −78° C. for 15 min, warmed to 0° C., and stirred for 1 h. Water (10 mL) was added and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 g) using 25% EtOAc in hexanes as the eluent to afford trimethoxyphenyl)acetyl)oxazolidin-2-one as a colorless oil (2.30 g, 88%): Rf=0.28 (1:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.55 (s, 2H), 4.44-4.41 (m, 1H), 4.29-4.24 (m, 2H), 4.19 (dd, J) 9.0, 3.0 Hz, 1H), 4.12-4.07 (m, 1H), 3.82 (s, 6H), 3.80 (s, 3H), 2.36-2.30 (m, 1H), 0.87 (d, J) 6.8 Hz, 3H), 0.78 (d, J) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 154.1, 153.2, 129.4, 106.7, 63.4, 60.9, 58.6, 56.2, 41.6, 28.4, 18.0, 14.7, 14.3; HRFAB[M+Li]344.1686 (calculated C17H23NO6Li: 344.1686).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[N:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:27]([O:24][CH2:23][C:19]1[N:18]=[C:17]([CH2:16][N:13]2[C:8]3[N:9]=[C:10]([N:12]([CH2:22][CH:17]=[CH2:16])[CH2:6][CH:2]=[CH2:3])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)[CH:22]=[CH:21][CH:20]=1)[CH:28]=[CH2:29]
Reactant: C=CCBr
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CO)n3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cccc(Cn2nnc3c(-c4ccco4)nc(N(CC=C)CC=C)nc32)n1
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A solution of 7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.377 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (30 mg, 0.743 mmol), stirred for 15 min, treated with allyl bromide (96 μl, 1.11 mmol), stirred at room temperature for 16 h, concentrated in vacuo to −2 mL and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (50 mg, 30%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=[CH2:3].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>CN(C=O)C>[CH2:1]([C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[N:6][C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(Cl)ncnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)ncnc1-c1ccccn1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
The 5-allyl-4,6-dichloropyrimidine (2 g) and 2-(tributylstannyl) pyridine (6.1 g) were dissolved in dry DMF (1.0 mL). The reaction mixture was degassed with nitrogen for 30 minute and Pd(PPh3)4 (615 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes before being irradiated under microwave at 160° C. for 30 minutes. The reaction mixture was cooled to room temperature, filtered through a celite pad and washed with ethyl acetate (2×50 mL). The combined filtrate was washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by column chromatography using EtOAc/hexane (0.4:9.6) as eluent to afford 5-allyl-4-chloro-6-(pyridin-2-yl)pyrimidine (1 g) as off white solid. 1H NMR (DMSO-d6): δ 3.80-3.82 (d, 2H), 4.83-4.89 (dd, 1H), 4.90-5.00 (dd, 1H), 5.82-5.88 (m, 1H), 7.53-7.57 (m, 1H), 7.90-8.04 (m, 2H), 8.69-8.71 (d, 1H), 9.0 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Br[CH2:11][CH2:12][F:13]>CN(C=O)C.O>[F:13][CH2:12][CH2:11][N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: FCCBr
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(CCF)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a suspension of sodium hydride (1.37 mol, (60% in oil) in DMF (350 mL) was added 3,5-dimethyl-1H-pyrazole (120 g, 1.25 mol). After this, the reaction mixture was stirred for 1 h at room temperature and treated with 1-bromo-2-fluoroethane (175 g, 1.37 mol) in DMF (200 mL). The reaction mixture was left to stir overnight, diluted with water (2 L), and the product was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (1 L), dried with sodium sulfate, and evaporated. The liquid residue (120 g) was chromatographed on a “Biotage” apparatus with silica gel using ethyl acetate/hexane (1:5) as the eluent (Rf=0.3) to give 88 g (49.7%) of the title product.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[C:2]#[CH:3].[C:7]1([SH:14])[C:8]([SH:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>C1COCC1.C(O[K])(C)(C)C>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:14][CH:3]1[CH2:2][C:1]([OH:5])=[O:4]
Reactant: C#CC(=O)OC
Reactant: Sc1ccccc1S
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(O)CC1Sc2ccccc2S1
Reaction time: 3 h

Procedure:
To a solution of methyl propiolate (0.75 mL) in THF (10 mL) were added a solution of benzene-1,2-dithiol (1.2 g) in THF (10 mL) and tert-butoxy potassium (catalytic amount) under ice-cooling, and the mixture was stirred at the same temperature for 3 hours and then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added methanol (5 mL) at room temperature, and then an aqueous solution (10 mL) of sodium hydroxide (0.45 g). The mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added ion-exchanged water (20 mL), which was washed with ethyl acetate. The aqueous layer was adjusted to pH 2 by addition of 1N hydrochloric acid, and then extracted with ethyl acetate (70 mL) twice. The organic layers were combined, washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2-(benzo[1,3]dithiol-2-yl)acetic acid (1.35 g) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC.CCCCCC>[CH2:12]([NH:19][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: NCc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(NCc1ccccc1)c1cc(Cl)ccn1

Procedure:
A mixture of 5 g of methyl 4-chloropicolinate and 3.44 g of benzylamine is heated at 100° for 16 hours. Cooling and trituration with ether/hexane affords N-benzyl-4-chloro-pyridine-2-carboxamide. This material is heated with 5 g of sodium azide in 50 ml of dimethylformamide at 100° for 10 hours. After dilution with water the product is extracted with ether. Drying and removing the solvent affords 4-azido-N-benzyl-pyridine-2-carboxamide as an oil. This material is stirred under 1 atom of hydrogen in 50 ml of ethanol with 1.0 g of 10% palladium on carbon catalyst for 4 hours. Filtration and removal of solvent affords 4-aminopyridine-2-(N-benzyl)-carboxamide as an oil.
Reaction SMILES: [C:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:14])[CH:4]=1)#[N:2].O=S(Cl)Cl.[CH3:19]O>>[C:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[C:5]([F:14])[CH:4]=1)#[N:2]
Reactant: CO
Reactant: COc1cc(C(=O)O)c(F)cc1C#N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)c(C#N)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Cyano-2-fluoro-5-methoxybenzoic acid (75 mg; 0.38 mmol; 1 eq.) was dissolved in MeOH (1 mL). The solution was cooled down to 0° C. SOCl2 (0.11 mL; 1.54 mmol; 4 eq.) was added dropwise. After addition, the reaction mixture was stirred at RT overnight. As the reaction was complete, solvents were evaporated. The crude mixture was dissolved in EtOAc and washed with NaHCO3 sat and brine. The organic phase was dried over MgSO4, filtrated and evaporated, affording the title product as an orange solid (64 mg; 80%). HPLC (Method A) Rt 3.68 min (Purity: 94.5%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:3][CH2:4]2)=[N:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(N2CCC(N)CC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(N2CCC(NC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 41 %

Procedure:
This compound was synthesized from 6-(4-aminopiperidin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (70 mg, yield 41%). 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2H), 8.27 (d, J=7.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.66-7.61 (m, 2H), 6.67 (d, J=9.0 Hz, 1H), 6.14 (d, J=7.8 Hz, 1H), 4.51-4.48 (m, 2H), 4.39-4.29 (m, 1H), 3.20-3.13 (m, 2H), 2.24-2.20 (dd, J=12.3 Hz, 2.3 Hz, 2H), 1.62-1.52 (m, 2H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Oc2ccccc2)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of commercially available (6-phenoxypyridin-3-yl)methanol (150 mg; 0.74 mmol) in anh. DCM (6 ml) was treated at rt with CBr4 (247 mg; 0.74 mmol), and with PPh3 (195 mg; 0.74 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 15 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 5-(bromomethyl)-2-phenoxypyridine as a pale yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 263.98 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=O)=[C:4]([CH3:14])[CH:3]=1.S(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:8][CH:9]2[CH2:10][CH2:11]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cc(Br)ccc1CNC1CC1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH3.SMe2 (1.08 g, 14.24 mmols). The solution was heated to 60° C. for 6 hours, cooled to room temperature and carefully treated with saturated aqueous Na2CO3 (30 mL) and stirred for 17 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with H2O, saturated aqueous NaCi before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-15% EtOAc-hexanes).