Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[CH:7]=1)#[N:2].Cl.CO.[NH3:16].[CH3:17][S:18]([OH:21])(=[O:20])=[O:19]>CO>[CH3:17][S:18]([OH:21])(=[O:20])=[O:19].[C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[CH:7]=1)(=[NH:16])[NH2:2]
Reactant: N
Reactant: N#Cc1cc2ccc(O)cc2o1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: N=C(N)c1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
2Cyano-6-hydroxybenzofuran (Rene, L.; Buisson, J.-P.; Royer. R. Reaction induites par le chlorhydrate de pyridine. XVI. -Sur la desalcoylation des derives Bz-methoxyles de nitriles et amides coumariliques. Bull. Soc. Chim. 1974, 475-476; 1.45 g, 9.11 mmol) was added to a cooled, saturated methanol-HCl solution (10 mL) and the mixture was stirred for 20 h at ambient temperature. The reaction mixture was concentrated in vacuo to give a solid. The solid was suspended in anhydrous methanol (40 mL) and gaseous NH3 was introduced into the mixture at 50° C. for 3 h to give a homogenous solution. The solvent was evaporated in vacuo, and the resulting solid was suspended in methanol (10 mL) and then treated with a saturated solution of NaHCO3 (30 mL). The precipitate was collected by filtration, washed with water (15 mL) and then dried in vacuo over P2O5 for 3 h. The solid (1.48 g) was suspended in 5 mL of methanol and then treated with methanesulfonic acid (1.1 g, 11.5 mmol). The precipitated material was recrystallized from methanol to give 1.62 g (65%) of 2-amidino-6-hydroxybenzofuran methanesulfonate as a brown solid, mp 253-254° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-chloro-3-nitro-benzoic acid (2 g, 1.0 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (50 mL) till all the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (1.8 g, 84.11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:16][CH:15]=1.Cl>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.61–6.92 (m, 11H), 5.24–5.16 (m, 1H), 3.70–3.58 (m, 2H), 3.02–2.91 (br, 2H), 2.80–2.64 (m, br, 3H), 2.64–2.50 (m, 3H), 2.18–1.94 (m, br, 6H), 1.62–1.44 (m, br, 2H) 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 605.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: C=CCCCBr
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 63%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 5-bromo-1-pentene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ1.68-1.79 (m, 2H), 2.01-2.26 (m, 7H), 2.43-2.62 (m, 4H), 2.71 (t, J=6.3 Hz, 2H), 2.83-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.27-3.44 (m, 3H), 3.86 (s, 3H), 4.93-5.05 (m, 2H), 5.70-5.85 (m, 1H), 6.80 (s, 1H), 6.84 (s, 1H), 7.02 (dd, J=8.1, 2.6 Hz, 1H), 7.18-7.24 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 107.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.0 g, 23.3 mmol) in dry tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium in n-hexane (1.6 M, 10 mL, 16 mmol). The mixture was stirred at −78° C. for 5 min and then treated with 4-methylsulfanylbenzaldehyde (2.4 g, 15.8 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×500 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with dichloromethane (2×5 mL) and dried in vacuo to afford (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol (7.0 g, 73%) as a white solid: LC/MS m/e calcd for C21H18N2O3S2 [M+H]+ 411.52, observed 411.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:34][O:35][CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][O:35][CH3:34])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:27][CH:28]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC/C=C/C(=O)O
Reactant: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Product: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)c1
Yield: 65.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide (intermediate 9) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (30.9 mg, 65.7%). Data: UPLC (C) R: 2.73 min; m/z 566.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:25])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(OCC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([O:25][C:30](=[O:32])[CH3:31])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a 500 mL round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 20 mmole), DCM (100 mL), TEA (3.0 g, 30 mmole), and DMAP (25 mg, 0.2 mmole). To the rapidly stirred suspension at room temperature was added acetic anhydride (2.3 g, 23 mmole). The reaction was complete after 10 minutes as determined by TLC analysis. The mixture was diluted with DCM (100 mL), and washed with saturated aqueous ammonium chloride. The aqueous layer was back-extracted with additional DCM (100 mL). The combined organic fractions were washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to give an amorphous orange solid. The crude product was re-dissolved in 5% MeOH/DCM (65 mL). To the stirred solution was added diethyl ether (200 mL), which resulted in the formation of a bright yellow precipitate. The stirred suspension was cooled over a salt/ice bath to −5° C., then filtered to recover the solids. The solids were washed sparingly with diethyl ether and collected to provide acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (6.94 g, 80.4%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37-7.34 (m, 3H), 7.25 (td, 1H, J1=2.7 Hz, J2=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17 (ddd, 1H, J1=6.3 Hz, J2=10.2 Hz, J3=16.8 Hz), 5.41 (app d, 1H, J=17.2 Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); ESMS (m/z): 435 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>C(O)(C)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 1-(4-pyridyl)piperazine (1.79 g), N-(4-bromoacetylphenyl)-4-methylphenylsulphonamide (3.68 g) and triethylamine (1.39 ml) in isopropanol (50 ml) was stirred for 18 hours. The precipitated solid was collected, triturated with dichloromethane, filtered and dried. This solid was further purified by flash chromatography on neutral alumina eluting successively with dichloromethane, 2.5% v/v methanol/dichloromethane then 5% v/v methanol/dichloromethane. Evaporation of the desired fractions to a small volume followed by addition of dichloromethane gave a crystalline solid. This solid was collected, washed with dichloromethane to give the title compound, 440 mg, as crystals: m.p. 168°-170° C.; NMR (d6DMSO) δ 8.14(2H,d), 7.86(2H,d), 7.71(2H,d), 7.35(2H,d), 7.18(2H,d), 6.80(2H,d), 3.79(2H,s), 3.31(4H,t), 2.59(4H,t), 2.33(3H,s); m/e 451 (M+H)+ ; calculated for C24H26N4O3S: C, 64.0; H, 5.8; N, 12.4. found C, 63.4; H, 5.7; N, 12.2%.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.CI.[C:13]([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH3:13])[C:4](=[O:10])[CH:3]=1.[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Agent: Cc1[nH]c(=O)cc(Br)c1C
Agent: [K+]
Solvent: CI
Product: Cc1c(Br)cc(=O)n(C)c1C

Procedure:
4-bromo-1,5,6-trimethylpyridin-2(1H)-one was prepared by alkylation of 4-bromo-5,6-dimethylpyridin-2(1H)-one with methyl iodide using K2CO3 following a procedure analogous to that described in Example 59 Step 1. 4-bromo-5,6-dimethylpyridin-2(1H)-one was prepared following the procedure described in McElroy, W. T. and DeShong, P. Org. Lett. 2003, 5, 4779.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C)[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C1(C)C=CC=CC=1>O>[C:28]1([O:27][C:25]([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN1CCC(c2noc3cccc(F)c23)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Oc1ccccc1)N1CCC(c2noc3cccc(F)c23)CC1
Yield: 63.3 %

Procedure:
A mixture of 1.74 g of 4-fluoro-3-(1-methyl-4-piperidyl)-1,2-benzisoxazole, 1.25 g of potassium carbonate, 1.40 g of phenyl chloroformate and 50.0 ml of toluene was stirred under reflux for 8.0 hrs. The mixture was poured into water and the toluene layer was separated, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by passing through a silica gel column (20:1), using 1% methanol in dichloromethane as the eluent. The eluent was evaporated and the residue solidified when scratched to yield a solid. The solid was recrystallized from petroleum-ether (bp 30°-60°) to yield 1.6 g (64%) of product, mp 108°-110°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:24]([N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-[(2-bromophenyl)carbamoyl]piperidine-1-carboxylate (8 mmol), benzylbromide (1.05 ml, 8.8 mmol) and Cs2CO3 (5.2 g, 16 mmol) in DMF (20 ml) is stirred at rt overnight. DMF is removed in vacuo and the residue is partitioned between H2O (40 ml) and EtOAc (40 ml). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C@H:12]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@H]1c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1c1ccc(F)cc1
Yield: 87.4 %

Procedure:
To (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (0.55 g, 1.90 mmol) in tetrahydrofuran (20 mL) was added methanesulfonyl chloride (0.158 mL, 2.05 mmol), followed by dropwise addition of diisopropylethylamine (0.50 g, 3.9 mmol) and N,N-dimethylpyridin-4-amine (10 mg). After 30 minutes the reaction was diluted with ethyl acetate (50 mL) and washed with 0.1 M hydrochloric acid (25 mL) then saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 1:4) to give (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-(methylsulfonyloxy)piperidine-1-carboxylate (0.62 g, 88% yield). 1H NMR (400 MHz, CDCl3): 7.19 (dd, 1H), 7.05 (t, 2H), 5.38 (d, 1H), 5.14 (m, 1H), 4.14 (m, 1H), 3.25 (m, 1H), 2.68 (m, 1H), 2.59 (s, 3H), 2.21 9M, 1H), 1.93 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:10]2[N:11]([CH2:16][CH2:17][CH3:18])[C:12](=[O:15])[C:13]3[NH:14][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:7][C:8]=3[N:9]=2)=[CH:26][CH:25]=1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(NCc2ccc(C(=O)OC)cc2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.15 g, 0.535 mmol) in N-methyl-pyrrolidone (1 ml) was added methyl-4-(amino methyl)benzoate hydrochloride (0.216 g, 1.07 mmol) followed by diisopropylethylamine (242 mg, 1.874 mmol) and the resulting reaction mixture was heated at 150° C. overnight. To the reaction mixture was added water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 5% methanol in dichloromethane as solvent system to give the product (0.11 g, 50%) as an off white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:19](=[O:21])[CH3:20])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(OC(C)C)ccn1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1cc(OC(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-isopropyloxy-2-methylpyridine (687 mg) in tetrahydrofuran (7 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 3.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.549 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(4-isopropyloxypyridin-2-yl)-propan-2-one (652 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[C:19]([F:20])=[C:18](Cl)[N:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[C:15]=1[Cl:26].[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[N:17]=[C:16]([C:22]([O:24][CH3:25])=[O:23])[C:15]=1[Cl:26]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc3[nH]ccc3c2)c(F)c(N)c1Cl
Temperature: 150 °C
Yield: 69.8 %

Procedure:
1H-Indol-5-ylboronic acid (220 mg, 1.4 mmol, 1.1 equiv) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (300 mg, 1.3 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by cesium fluoride (380 mg, 2.5 mmol, 2.0 equiv), palladium(II) acetate (14 mg, 0.063 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (71 mg, 0.13 mmol, 0.10 equiv). A 3:1 mixture of water:acetonitrile (2.5 mL) was added and the resulting dark brown mixture was placed in a Biotage microwave and heated to 150° C. for 5 m, with external IR-sensor temperature monitoring from the side of the vessel. The cooled reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (15×30 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to yield the title compound as a tan powder (290 mg, 73%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a suspension of 1,5-diaminopentane dihydrochloride (2.9 g, 16.7 mmol) in THF (100 mL) was added 20% aqueous sodium hydroxide (10.0 g, 50 mmol) at 0° C. A solution of benzyl chloroformate (1.7 g, 10 mmol) in THF (10 mL) was added rapidly dropwise and the resulting mixture stirred at RT. After 1 h, the organic layer was separated and concentrated to give a residue which was dissolved in ethyl acetate (200 mL). This solution was extracted with water (3×50 mL.), dried (sodium sulfate) and concentrated. The residue was redissolved in ether (50 mL) and 1.0 ethereal hydrogen chloride (3.0 mL) was added. The resulting precipitate was filtered, suspended in CH2Cl2 (75 mL) and shaken with 5% sodium hydroxide (15 mL). The organic layer was washed with water (75 mL), dried (sodium sulfate) and concentrated to give the title compound 0.25 g, 30%): 1H NMR (400 MHz, CDCl3) δ7.15-7.4 (m, 5H), 5.15-5.4 (m, 1H), 5.05 (s, 2H), 3.05-3.2 (m, 2H), 2.55-2.7 (m, 2H), 1.2-1.5 (m, 6H).