Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(O[K])(C)(C)C>C(O)(C)(C)C.O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:14]2[C:11]3=[N:12][CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:34][CH:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:7]=[CH:6][CH:5]=4)[CH:9]=[C:10]3[C:16]([CH3:17])=[N:15]2)=[CH:20][CH:21]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)c4)cnc32)cc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(NC5CCN(C)CC5)c4)cnc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a stirred solution of 5-(3-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (96) (50 mg, 0.137 mmol) in tert-BuOH (4 mL), 1,4 dioxane (6 mL) was added 1-methylpiperidin-4-amine (16) (14 mg, 0.23 mmol, 0.9 eq) and tert-BuOK (38 mg, 0.344 mmol, 2.5 eq). The resulting reaction mixture was degassed, purged with N2 for 10 min and Pd2(dba)3 (5 mg, 0.00549 mmol, 0.04 eq) and tertButyl X-phos (0.08 eq) was added, the mixture was degassed and purged with nitrogen for 15 min. The reaction mixture was stirred overnight at 80° C. under sealed condition for 16 h. After completion of the reaction the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and solvent completely distilled off to get the crude. The crude was passed through 100-200 mesh silica gel. Eluting the pure compound at 5% MeOH/CHCl3 gave 25 mg of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-1-methylpiperidin-4-amine 97.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:51]2[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH:52]=2)O1>>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:3][C:2]([C:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH:52]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(C3=CCNCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, and was isolated as a bright yellow amorphous solid (13%). m/z (ESI, +ve ion) 391.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.74 (1H, br. s.); 8.81 (1H, br. s.); 8.54 (1H, br. s.); 8.40 (1H, br. s.); 8.17 (1H, br. s.); 7.88 (1H, br. s.); 7.73 (1H, br. s.); 6.83 (1H, br. s.); 6.17 (1H, d, J=1.0 Hz); 3.84 (3H, s); 2.93 (2H, br. s.); 2.44 (4H, br. s.); 1.56 (4H, s).
Reaction SMILES: NC1SC(C2C=CC=CC=2)=CC=1C(OC)=O.C(CC(OC)=O)#N.C(Cl)(=O)C1C=CC=CC=1.[C:33]([CH2:36][C:37]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:39][C:38]=1[NH:48][C:49]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:50])([OH:35])=[O:34]>CN(C)P(N(C)C)(N(C)C)=O.O>[C:33]([CH2:36][C:37]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:39][C:38]=1[NH:48][C:49](=[O:50])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([OH:35])=[O:34]
Reactant: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)C1CCCCC1
Agent: COC(=O)CC#N
Agent: COC(=O)c1cc(-c2ccccc2)sc1N
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Methyl 2-amino-5-phenyl-thiophene-3-carboxylate (1.3 g, 0.0055 mole) in hexamethyl phosphoramide (prepared by the method of Chemische Berichte, 99, 94 (1966) but using methyl cyanoacetate in place of ethyl cyanoacetate) (20 ml.) was stirred and treated with benzoyl chloride (1.56 g, 1.28 ml, 0.011 mole). The solution was stirred for 2 hours, poured into water (750 ml), stored overnight and the title compound filtered off (1.31 g) m.p. 190° C. Similarly prepared was: N-(3-Carboxymethyl-5-phenyl-2-thienyl) cyclohexane carboxamide, m.p. 121°-122° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[O:7].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:7]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)/C=C/CC(=O)c1ccco1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.02 moles of 4-(2-furoyl)crotonic acid in 100 ml. of tetrahydrofuran is added 0.022 moles of N,N'-carbonyldiimidazole. The mixture is stirred for 3 hours at room temperature and 0.021 moles of L-proline are added. The mixture is refluxed for 2 hours and stirred at room temperature for 16 hours to give 1-[4-(2-furoyl)crotonyl]-L-proline.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].C(N(CC)CC)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CSc2nc3ccccc3s2)cc1

Procedure:
To a solution of 2-benzothiazolthiol (250 g) in N,N-dimethylformamide (1 1) was added triethylamine (208 ml) under ice-cooling and dropwise a solution of benzyl bromide (178 ml) in N,N-dimethylformamide (300 ml) and the mixture was stirred for 40 minutes. The resulting solution was poured into water (10 l) and the formed precipitate was separated by filtration and dissolved in dichloromethane (3 l). After drying over anhydorpus magnesium sulfate, dichloromethane was removed in vacuo to give 378 g of the objective compound.
Reaction SMILES: [Na].O.S(O)(O)(=O)=O.[OH:8][NH:9][C:10]([NH2:12])=[NH:11].O[NH:14]C(N)=N.O.C(NC(=O)/C=C(\[O:28][C:29]([C:31]1[C:36](N)=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=O)/C)(C)(C)C>CC(O)C>[NH2:14][NH:11][C:10](=[NH:12])[NH:9][O:8][C:29]([C:31]1[CH:36]=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=[O:28]
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Reactant: N=C(N)NO
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: N=C(NN)NOC(=O)c1cnc(N)c(Cl)n1

Procedure:
Sodium metal (3.1 g., 0.135 g.at.) is dissolved in 2-propanol (500 ml.) and hydroxyguanidine hemisulfate hydrate (20.0 g., 0.075 mole) is added. The reaction mixture is heated at reflux for 1 hour then treated with N-t-butyl-3-(3,5-diamino-6-chloropyrazinecarbonyloxy)-crotonamide (20.5 g., 0.06 mole) heated at reflux for an additional hour to give product which is filtered, washed with water and dried. 3,5-Diamino-6-chloropyrazinecarbonyloxyguanidine melts at 192°-3° C. after purification by precipitation from dilute aqueous methanesulfonic acid with aqueous ammonia.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH:8]([CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:9][OH:10].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH3:13][C:12]1([CH3:14])[CH2:11][CH:8]([CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]2([CH3:15])[CH3:1])[CH2:9][O:10]1
Reactant: C=C(C)CC(CO)C1CC=C(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Product: CC1=CCC(C2COC(C)(C)C2)C1(C)C
Yield: 91.6 %

Procedure:
A 500 ml 3 neck round bottomed flask was charged with 56.1 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)-4-methyl-4-pentenol, (0.26 mole), 260 ml of hexane, and 0.75 g of p-TSA. The mixture was then refluxed for 7 hours. After cooling the batch was washed with 250 ml of 10% sodium carbonate, and once with 250 ml of brine. The batch was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was distilled through a 10 cm micro Vigreaux column to afford 49.6 g of purified product (90% yield). BP 51°-52° C./0.2 mmHg; 1H-NMR (300 MHz), δ 0.85 (3H, s), 0.95 (3H, s), 1.22 (3H, s), 1.27 (3H, s), 1.45 (1H, m), 1.58 (3H, s), 1.73 (1H, m), 1.83-2.0 (2H, m), 2.15 (1H, m), 2.40 (1H, m), 3.46 (1H, m, B part of ABX, JAB =6.63 Hz, JBX =6.63 Hz), 4.07 (1H, t, A part of ABX, JAB =6.63 Hz, JAX =6.63 Hz), 5.21 (1H, s), 13C-NMR (75 MHz), δ 12.59, 19.93, 26.57, 28.87, 29.09, 35.42, 42.06, 45.82, 47.09, 54.39, 72.08, 79.67, 121.98, 149.07; IR (Neat), 2980, 1055 cm-1 ; MS (m/e), 208 (M+), 193, 177, 43 (Base);
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:11](O)[C:12](=[CH2:21])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].S(Br)([Br:25])=O.O>ClCCl>[CH:1]([NH:3][CH:4]([CH:11]=[C:12]([CH2:21][Br:25])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCCC(=O)OCC)C(O)C(CC(=O)OCC)NC=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCC(=CC(CC(=O)OCC)NC=O)CBr
Reaction time: 1 h

Procedure:
10.3 g (35.9 mmol) of diethyl 2-formylamino-3-hydroxy-4-methylene-heptane-1,7-dicarboxylate are dissolved in 100 ml of dichloromethane and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise to the solution at room temperature. After 1 hour, 10 ml of water are added and the batch is thoroughly stirred. The organic phase is separated, washed in succession with water, saturated potassium hydrogencarbonate solution and again with water, dried over magnesium sulfate and concentrated by evaporation, giving diethyl 2-formylamino-4-bromomethyl-hept-3-ene-1,7-dicarboxylate as a brownish oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](Cl)=[S:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[S:29])=[CH:23][CH:22]=1
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 7.8, Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine and chloro-thioformic acid (4-chloro-phenyl)ester were converted to yield 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as light grey waxy solid, MS: 431 (MH+, 1Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F-].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:3]=1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1nn(-c2cccc(-c3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 90 °C

Procedure:
1-(3-Bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol), phenylboronic acid (37 mg, 0.31 mmol), cesium fluoride (124 mg, 0.82 mmol) are taken in dioxane-water (2:1) and bubbled with nitrogen for 5 min. Then bis(triphenyl phosphine)dichloro palladium(II) (21 g, 0.03 mmol) is added to reaction mass and heated under microwave irradiation for 1 h at 90° C. The reaction mixture is filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.03-8.01 (m,1H), 7.95-7.93 (d, J=8.0 Hz, 1H),7.83 (s, 1H), 7.72-7.70 (m, 4H), 7.68-7.60 (m, 2H), 7.59-7.47 (m, 3H), 7.45-7.40 (m, 1H), 4.91 (s, 2H), 3.96 (m, 4H), 3.62-3.61 (m, 2H). MS (ESI+): 486.0. HPLC (max plot) 98.53%; Rt 4.84 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH2:16][F:17])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:17][CH2:16][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH2:13][OH:14]
Reactant: CC(CF)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CO)(CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-3-fluoro-2-methylpropanoic acid (1.1 g, 4.9 mmol) in THF (16 ml) was cooled to 0° C., and triethylamine (518 mg, 6.1 mmol) was added, then ethyl chloroformate (663 mg, 6.11 mmol). A solution of sodium borohydride (370 mg, 9.8 mmol) in water (4 ml) was added, and the reaction warmed to RT over 4 h. The reaction was quenched with 1 M HCl, and extracted with EtOAc. The organic layers were combined, washed with sat. NaCl, dried on Na2SO4, and concentrated in vacuo. Flash chromatography (0% to 10% MeOH in DCM) afforded the title compound as a clear oil (915 mg, 77%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 3H), 3.4 (br s, 1H), 3.72-3.80 (m, 2H) 4.47 (dd, J=9.6, 18.4 Hz, 1H), 4.60 (dd, J=9.2, 18.8 Hz, 1H), 5.12 (s, 2H), 5.32 (s, 1H), 7.28-7.37 (m, 5H). 19F NMR (CDCl3, 376 MHz) δ −231.2 (t, J=48.9 Hz). 13C NMR (CDCl3, 100 MHz) δ 19.2 (d, J=4 Hz), 56.8 (d, J=17 Hz), 66.4 (d, J=4 Hz), 66.9, 85 (d, J=173 Hz), 128.1, 128.3, 128.6, 128.6, 136.0, 156.0.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[S:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].IC>C(O)C>[C:14]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:11][CH:10]([S:12][CH3:20])[NH:9][C:8]2=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=S)NC1(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSC1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Yield: 60 %

Procedure:
7.0 g of 5,5-diphenyl-2-thiohydantoin is dissolved in 50 ml of ethanol and 10 ml of 3N sodium carbonate added followed by 3 ml of iodomethane. The mixture is refluxed for 18 hours, then cooled and the solvent evaporated. The residual solid is recrystallized from ethanol to give 4.6 g (60%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[SH:8].[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][Cl:28])[CH2:21][CH2:20]2)[CH:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[N:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[ClH:28].[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][S:8][C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[N:5][N:4]=3)[CH2:21][CH2:20]2)[CH:16]=[C:15]([C:29]([F:30])([F:31])[F:32])[N:14]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1nnc(S)n1C
Reactant: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C(F)(F)F)n1
Product: Cc1nnc(SCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)n1C
Product: Cl
Yield: 75.8 %

Procedure:
3 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (23.22 mmol) were reacted with 8.47 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (23.22 mmol) to yield 8.7 g of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCNC[C@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 186 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([CH3:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Yield: 66 %

Procedure:
Compound 217b was synthesized from compound 201b and compound 214 as a beige solid in 66% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=333 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([C:12]3[N:16]([CH3:17])[N:15]=[C:14]([CH:18]4[CH2:20][CH2:19]4)[CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:22][C@@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1.[CH3:29]CN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@H:23]2[CH3:22])[C:5]2[CH2:11][N:10]([C:12]3[N:16]([CH2:17][CH3:29])[N:15]=[C:14]([CH:18]4[CH2:20][CH2:19]4)[CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@@H]1COCCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(C2CC2)cc1N1CCc2nc(Cl)nc(Cl)c2C1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1nc(C2CC2)cc1N1CCc2nc(Cl)nc(N3CCOC[C@H]3C)c2C1
Temperature: 110 °C

Procedure:
To a solution of 2,4-dichloro-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.110 g, 0.325 mmol) in DMA (2.2 mL) was added (R)-3-methylmorpholine (49.3 mg, 0.488 mmol) and DIPEA (284 μL, 1.63 mmol). The mixture was heated at 110° C. for 2 h. Water was added and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, washed with brine (3×), dried with sodium sulfate, filtered and concentrated under reduce pressure. Purification by FCC (0-60% EtOAc/heptane) provided the title compound (R)-4-(2-chloro-6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine. MS (ESI+) m/z 403.1 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH:49]([Mg]Br)=[CH2:50]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:6]([CH2:5][C:4](=[O:47])[CH:49]=[CH2:50])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=C[Mg]Br
Product: C=CC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b, using N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) and vinyl magnesiumbromide to afford the title compound as a yellow oil. Rf=0.50 (EtOAc-heptane 1:1); Rt=5.23.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10](Cl)[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1.[NH3:20]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[NH2:20])=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(Br)cc1
Solvent: C1CCOC1
Product: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a cold solution of N-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbohydrazonoyl chloride (0.070 g, 0.267 mmol) in dry THF was added aq. ammonia. The reaction mass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched in water, neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.29 (br s, 2H), 6.80 (d, J=8.4 Hz, 2H), 7.24 (d, J=9.3 Hz, 2H), 7.28-7.50 (m, 3H), 8.33 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].[C:13]([OH:21])(=[O:20])[CH:14]([CH2:16][C:17]([OH:19])=[O:18])[OH:15].CO>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:13]([O-:21])(=[O:20])[CH:14]([CH2:16][C:17]([O-:19])=[O:18])[OH:15]
Reactant: CN(C)C(=N)N=C(N)N
Reactant: O=C(O)CC(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CN(C)C(=N)NC(=N)N
Product: O=C([O-])CC(O)C(=O)[O-]
Yield: 113.3 %

Procedure:
12.5 g (2.5 molar equivalents) of metformin hydrochloride, 3.02 g (2.5 molar equivalents) of sodium hydroxide and 4.05 g (1 molar equivalent) of malic acid were stirred in a mixed solution of methanol and ethanol (1:1) at 40° C., and then the produced crystal was filtered. The produced crystal was stirred in ethanol at 50, and the stirred at 10° C. for 5 hours. Then, the crystal was filtered and dried in hot air, thus obtaining 8.94 g (yield: 75.4%) of metformin malate.