Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.BrBr.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1>C(O)(=O)C.C(OC)(C)(C)C>[BrH:1].[Br:1][CH:5]1[C:6]([C:15]2[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][CH2:8][N:3]([CH3:2])[CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(OC)cc(OC)c1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
75.7 ml (0.44 mol) of 33% strength HBr in glacial acetic acid were added to 200 ml of glacial acetic acid, and 50 g (0.44 mol) of 1-methylpiperidin-4-one (III) were then rapidly added dropwise at 20-25° C. with ice-cooling. 70.4 g (0.44 mol) of bromine were added dropwise at 20-25° C. in the course of 30 min to the suspension of the hydrobromide obtained in this way, a clear, yellowish solution being obtained. This was stirred at 25° C. for a further 15 min and 67.2 g (0.40 mol) of 1,3,5-trimethoxybenzene (V) were then added to the reaction solution. It was then stirred at 25° C. for 1 h. After this, 300 ml of methyl tert-butyl ether were allowed to run in, the product being deposited in oily form. The supernatant was decanted off, the residue was stirred again with 300 ml of methyl tert-butyl ether and the supernatant was decanted off. The residue was then stirred with 150 ml of dichloromethane, the product crystallizing out. The 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) obtained was filtered off with suction, washed with 50 ml of dichloromethane and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[CH:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[CH:19]([NH:21][S:42]([CH:39]4[CH2:41][CH2:40]4)(=[O:44])=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)NS(=O)(=O)C2CC2)cc1
Temperature: 25 °C

Procedure:
The racemic mixture of (1RS,2SR)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (27a, 11 mg, 0.02 mmol) was dissolved in THF (1.5 mL). Excess N-ethyldiisopropylamine (0.185 mL, 1.1 mmol) and cyclopropanesulfonyl chloride (0.063 mL, 0.62 mmol) was added in portions over a period of 3 hours. The reaction mixture was stirred over night at room temperature, quenched by addition of water and purified by HPLC. Fractions with product was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm. two peaks was seen in 1:1 ratio.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([Cl:19])=[N:14]3)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]3[CH:28]=[CH:27][C:26]4[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH:30]=3)(=[O:35])=[O:34])[C:4]2=[O:20])[N:14]=1
Reactant: N[C@H]1CCN(Cc2cccc3nc(Cl)ccc23)C1=O
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc5nc(Cl)ccc45)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 5-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride in place of 7-(3-(S)-amino-2oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is purified by column chromatography eluting with 25% EtOAc/CH2Cl2 to provide the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[O:43]1[C:44]2[CH:45]=[CH:46][C:38]([CH2:37][NH:47][C:23](=[O:24])[CH:22]([N:8]3[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=4[CH:7]3[CH2:6][C:5]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:39][C:40]=2[O:41][CH2:42]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc3c(c2)OCO3)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with piperonylamine.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.[C:20](OCC)(=[O:22])[CH3:21].O.C(O)=O>CN(C)C=O>[CH3:21][C:20]([O:9][C@@H:8]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:16]([C:17]([NH2:19])=[O:18])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:22]
Reactant: CCOC(C)=O
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 29 h

Procedure:
In a 250 ml flask with overhead stirrer, reflux condenser and under nitrogen were combined: 16 g oxcarbazepine (63 mmol, 1 mol eq), 120 ml of ethyl acetate, 35 g IRA-67 tertiary ion exchange resin (SigmaAldrich, cat 476633), 10 ml water and 4.4 g formic acid (96 mmol, 1.5 mol eq). 35 mg RuCl [(S,S)-Ts-DPEN](p-cymene) (SigmaAldrich #703915) was dissolved in 10 ml dimethylformamide and added to the reactor. The reaction was heated in an oil bath to reflux. After 29 hours, without any further formic acid addition, the conversion had reached 98,4%. Product was isolated by filtering off the resin and washing with a 20 ml ethyl acetate. The combined organic phases were then washed with 10 ml water which was separated off. After cooling in the fridge, the product was filtered off and washed twice with 15 ml ethyl acetate. The isolated product had an ee of 98%. After acetylation and crystallisation using a similar method to that described in Example 3, eslicarbazepine acetate was isolated with an ee of 99.8% and product purity of 99.9% (HPLC area %, 210 nm).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) was added to a suspension of sodium hydride (60 wt %, 0.238 g, 5.96 mmol) in DMF (16.56 mL) and stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (1.11 g, 7.45 mmol) was added to the reaction mixture and stirred for 2 hours at room temperature. The mixture was then diluted with ethyl acetate (100 mL) and washed with 1:1 water:brine (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26][CH:25]=[C:24]([CH3:27])[CH2:23][CH2:22][CH:21]=[C:20]([CH3:28])[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [CH2:1]([NH:5][CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:22](OC(=O)C)(=O)[CH3:23]>>[CH2:1]([N:5]([CH2:22][CH3:23])[CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCNC(CO)CCOc1cccc2ccccc12
Product: CCCCN(CC)C(CO)CCOc1cccc2ccccc12

Procedure:
2-(butylamino)-4-(1-naphthyloxy)-1-butanol, described in Example 6, with acetic anhydride, followed by reduction, gives 2-(butylethylamino)-4-(1-naphthyloxyl)-1-butanol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C([O-])([O-])=O.[Ca+2].CCN(CC)CC>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:4]1[N:3]=[C:2]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc(C)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C)nc1Nc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
1-(2-Chloro-6-methyl-pyridin-3-yl)-ethanone (0.4 g) was mixed with 3-nitro-phenylamine (0.33 g), Pd(OAc)2 (16 mg), BINAP (45 mg), CaCO3 (0.25 g), and Et3N (0.2 mL) in toluene (10 mL), and heated at 100° C. for 4 d. The product was then filtered and concentrated to provide 1-[6-methyl-2-(3-nitrophenylamino)-pyridin-3-yl]-ethanone (0.2 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.CN>CN(C)C=O>[CH3:21][NH:23][C:18]([CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[O:20]
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 61.5 h
Yield: 74.1 %

Procedure:
To a solution of 1-benzhydrylazetidin-3-carboxylic acid (654 mg) in N,N-dimethylformamide (4.0 ml) were added triethylamine (1.0 ml), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.63 g) and methylamine hydrochloride (248 mg), followed by stirring at room temperature for 61.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (509 mg, 74.1%) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[C:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)[O:9][CH2:10][CH2:11]I)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH3:28]>C(=O)=O>[NH2:28][CH2:11][CH2:10][O:9][C:8](=[C:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Reactant: N
Agent: O=C=O
Solvent: C1CCOC1
Product: NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1
Temperature: 40 °C
Yield: 90 %

Procedure:
##STR37## A solution of alkene 9 (3.0 g, 0.01 mol) in a minimum amount of THF was added into 10 mL of liquid ammonia in a sealed tube which was kept in dry ice. After sealing the tube this was heated at 40° C. in an oil bath for 17 hours. The reaction mixture was cooled down and solvent evaporated to obtain a white solid. This material was extracted with methylene chloride. The combined organic layers were washed with water, dried over MgSO4, and concentrated to give 2.0 g (90%) of alkene 10 as a white solid: mp 55° C., 1H NMR (CDCl3) δ 8 1.77-1.96 (m, 12H), 2.68 (bs, 1H), 2.85 (t, 2H, J=4.8 Hz), 3.23 (bs, 1H), 3.48 (t, 2H, J=4.8 Hz), 4.46 (bs, 2H), 6.70-7.17 (m, 4H); 13C NMR (CDCl3) δ 28.16, 30.28, 32.19, 36.99, 38.88, 39.04, 41.33, 70.45, 114.97, 116.17, 120.63, 129,02, 131.89, 136.69, 141.79, 156.86; MS m/e (rel intensity) 299 (10), 256 (100), 239 (5), 199 (6), 135 (12), 121 (27), 93 (12), 77 (5); MS exact mass: calcd. 299.1885, found 299.1891.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1.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>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(B(O)O)ccc1Cl
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccn2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of commercially available 2-bromopyridine (294 mg; 1.86 mmol), 4-chloro-3-(methoxycarbonyl)phenylboronic acid (400 mg; 1.86 mmol), K2CO3 (515 mg; 3.73 mmol), and PdCl2(PPh3)2 (130 mg; 0.18 mmol) in THF (4 ml) and water (4 ml) was stirred at rt, under nitrogen, for 20 h. Water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-chloro-5-(pyridin-2-yl)benzoate as a colorless solid. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 248.02 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19]([Cl:28])=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298 g, 0.00075 mol) and potassium carbonate (0.311 g, 0.0023 mol), were taken in DMF (2 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.4 ml, 0.0023 mol) was added drop wise at 0° C. and the mixture was stirred at 20° C. for 4 hours. The mixture was cooled to 10° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layer was washed with saturated brine solution (2×15 ml) and dried over Na2SO4. Solvent was removed and the residue was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.278 g, 70%) as off white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)[CH:3]=1.[O:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[C:14]([CH:13]=[CH:12][N:11]=3)[C:16]#[N:17])[CH:3]=2)[CH2:22][CH2:23]1
Reactant: Cc1cc(Cl)cc(Nc2cc(C#N)ccn2)n1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Product: Cc1cc(C2=CCOCC2)cc(Nc2cc(C#N)ccn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Into a vial was weighed 2-[(4-chloro-6-methyl-2-pyridyl)amino]pyridine-4-carbonitrile (282 mg, 1.15 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85.1 mg, 10 mol %), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (374 mg, 1.73 mmol) and potassium carbonate (478 mg, 3.46 mmol). After purging with nitrogen, the vial was charged with degassed 1,4-dioxane (2.3 mL) and degassed water (1 mL) and the reaction mixture was stirred at 80° C. overnight. The reaction was barely progressing at all as determined by RPLC and so bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (˜50 mg) and more 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (374 mg, 1.73 mmol) was added and the reaction temperature was increased to 100° C. and stirred overnight again. After cooling to rt and filtration through Celite, rinsing with CH2Cl2, the mother liquor was washed with brine and dried over MgSO4. Purification by flash column chromatography (100:0-95:5 CH2Cl2/MeOH) afforded 2-((4-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyridin-2-yl)amino)isonicotinonitrile as a red solid (206 mg, 61%); 1H NMR (400 MHz, DMSO) δ 10.07 (br s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 7.51 (s, 1H), 7.23 (d, J=5.0 Hz, 1H), 6.93 (s, 1H), 6.45 (s, 1H), 4.25 (s, 2H), 3.83 (m, 2H), 2.43 (s, 3H), 2.41 (m, 2H); ESI-LRMS m/z [M+1]+=293.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:27])[C@H:16]([CH2:25][OH:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.CCCCCC.[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([O:8][C:9](=[O:28])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:27])[C@H:16]([CH2:25][OH:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
N-t-butyloxycarbonyl-L-seryl-L-proline benzylester (33.99 g, 86.6 mmole) was dissolved in 4N hydrochloric acid in dioxane (300 ml) solution, and stirred for 1 hour at room temperature. To the solution, diethyl ether (500 ml) and n-hexane (100ml) were added to give L-seryl-L-proline benzylester hydrochloride (yield: 28.03 g, 98.4%).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>C(O)(=O)C>[CH2:16]([O:20][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1)[C:17]#[C:18][CH3:19]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To 70 ml of N,N-dimethylformamide, 3.00 g (19 mmol) of 6-chloronicotinic acid and 2.00 g (29 mmol) of 2-butyne-1-ol were dissolved, followed by adding 1.80 g (45 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and stirring at 140° C. for 3 hours. The reaction liquid was then poured in 150 ml of ice water, and acetic acid was added to make pH 5, followed by adding 50 ml of a saturated saline solution. The crystal precipitated was filtered, washed with cold water and hexane and dried to obtain 0.96 g (yield: 26%) of 6-(2-butynyloxy)nicotinic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C1(N(C)C2CCCCC2)CCCCC1>[Cl-].C([N+](CC)(CC)CC)C.CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH3:14])=[O:12])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(F)cc1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A mixture of 1-bromo-4-fluorobenzene (10 g, 57 mmol), methyl acrylate (4.5 g, 52 mmol), tetraethylammonium chloride (8.6 g, 52 mmol), N-cyclohexyl-N-methylcyclohexanamine (15 g, 78 mmol), and palladium (II) acetate (0.35 g, 1.6 mmol) in dimethylacetamide (200 mL) was heated to 100° C. under an argon atmosphere. The reaction was allowed to proceed until the aryl halide was consumed. The reaction mixture was then cooled to room temperature, diluted with Et2O, and washed three times with water. The separated organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes to afford 8.5 g (91% yield) of the title compound.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([NH:6][S:7]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1)(=[O:9])=[O:8])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:1]([N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=[C:10]1[S:7]([NH:6][CH2:4][CH3:5])(=[O:9])=[O:8])[CH3:2]
Reactant: CCNS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCNS(=O)(=O)c1nc2ccccc2n1CC
Yield: 74.7 %

Procedure:
46.8 g (0.3 mol) of ethyl iodide are added to a suspension of 67.5 g (0.3 mol) of N-ethyl-1H-benzimidazole-sulfonamide and 47.7 g (0.45 mol) of sodium carbonate In 450 ml of acetone and 20 ml of water. The mixture is left under reflux for 20 hours, the acetone is evaporated off, 200 ml of water are added and the product is extracted with methylene chloride. The organic layer is dried (Na2SO4) and evaporated. The residue is recrystallized from an ethanol/water mixture (2:1) to give 56.8 g (75%) of 1,N-diethyl-1H-benzimidazole-2-sulfonamide melting at 135°-9° C.