Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(Cl)n1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(C)nc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 5-(2-Chloro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep107, 345 mg, 1.27 mmol), K2CO3 (174 mg, 1.27 mmol) and 3-bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) in DMF (3 ml) was stirred at room temperature overnight. 3-Bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) was then added and the reaction mixture stirred for additional 2 days. Water was added and the aqueous layer washed with diethylether and then the product extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with ethyl acetate-NH4OH (100-0.25) to give 90 mg of the title compound (21% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5](C#N)=[CH:4][N:3]=1.[C:31]([O-:34])(O)=[O:32].[Na+]>O1CCOCC1.S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5]([C:31]([OH:34])=[O:32])=[CH:4][N:3]=1
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1C(=O)O)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (53) (495 mg, 1.19 mmol) in anhydrous 1,4-dioxane (20 mL), sulfuric acid/water (1:1, 7 mL) was added dropwise. The reaction mixture was stirred at 90° C. for 60 h. The mixture was allowed to cool to RT and basified with NaHCO3. The precipitate was collected by filtration and then dissolved in water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 117, (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylic acid. The material was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.O/[N:27]=[C:28](/[NH2:31])\[CH2:29][CH3:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9]2[O:10][N:31]=[C:28]([CH2:29][CH3:30])[N:27]=2)[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CC/C(N)=N\O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1noc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)n1
Reaction time: 24 h
Yield: 1 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo [c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (0.5 g, 1.4 mmol) and (E)-N′-hydroxypropionimidamide (0.19 mL, 2.1 mmol) in 10 mL of DMF was added EDC (0.5 g, 3.6 mmol) and HOBt (700 mg, 3.6 mmol). The reaction mixture was stirred for 24 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (6 mg, yield 13%), and cyclized product (7 mg, yield 1%). 4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-((3-ethyl-1,2,4-oxadiazol-5-yl)methyl)benzenesulfonamide: MS calcd for (C18H19BN4O5S): 414.24. MS found (ESI negative): (M−H)−=413.1. 1H NMR (DMSO-d6) δ (ppm): 10.0 (s, 1H), 9.18 (bs, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8 Hz, 1H), 7.08 (dd, J=8, 2 Hz, 1H), 6.45 (dd, J=8.8, 2 Hz, 1H, 6.39 (d, J=3 Hz, 1H), 4.86 (s, 2H), 4.48 (s, 2H), 2.63 (q, J=7.6 Hz 2H), 1.17 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][C:14]([F:17])([F:16])[F:15])[C:5]=1[OH:18])[CH:2]=[CH2:3].[CH3:19]I>>[CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][C:14]([F:16])([F:17])[F:15])[C:5]=1[O:18][CH3:19])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCc1cc([N+](=O)[O-])cc(OC(F)(F)F)c1O
Product: C=CCc1cc([N+](=O)[O-])cc(OC(F)(F)F)c1OC
Reaction time: 17 h

Procedure:
1-Allyl-2-methoxy-5-nitro-3-trifluoromethoxybenzene was prepared from 2-allyl-4-nitro-6-trifluoromethoxyphenol and methyl iodide by following Method C. The reaction was conducted at room temperature for 17 h. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (0-5%) as an eluent to give 1-allyl-2-methoxy-5-nitro-3-trifluoromethoxybenzene in 52% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](Cl)=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=1)[CH2:26][NH2:27]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([NH:27][CH2:26][C:25]1[CH:28]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:29][CH3:30])=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1CN
Reactant: Clc1ccc2c(OCc3ccccc3)cccc2n1
Product: COc1ccc(F)cc1CNc1ccc2c(OCc3ccccc3)cccc2n1

Procedure:
5-Benzyloxy-2-chloroquinoline (155 mg, 0.56 mmol) and 5-Fluoro-2-methoxybenzylamine (CAS 1978-39-8) (268 mg, 1.68 mmol) were stirred in a sealed tube at 90° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->50:50 gradient). (5-Benzyloxy-quinolin-2-yl)-(5-fluoro-2-methoxy-benzyl)-amine was obtained as a colorless oil (40 mg, 18%),
Reaction SMILES: Cl.[Cl:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH2:13][NH2:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([Cl:2])([CH2:10]3)[CH2:4]1)[CH2:6]2)=[O:19]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCC12CC3CC(CC(Cl)(C3)C1)C2
Agent: Cl
Product: O=C(NCC12CC3CC(CC(Cl)(C3)C1)C2)c1ccccc1Cl

Procedure:
Prepared according to the method of Example 1 from 3-chloro-tricyclo[3.3.1.13,7]decane-1-methanamine, hydrochloride (0.061 g) and 2-chlorobenzoyl chloride (0.0.32 ml) to give the title compound as a white solid (0.093 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:15][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: BrCCCBr
Reactant: COc1ccc(Br)c(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c2c1OCCCO2
Temperature: 110 °C
Reaction time: 12 h

Procedure:
3-bromo-6-methoxycatechol (31 g) was dissolved in DMF (50 ml), mixed with 1,3-dibromopropane (36 ml) and potassium fluoride (42 g), stirred for 12 hours while heating at 110° C. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed with an aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give Compound IIbr-a (6.7 g, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3)c2)cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3Cc3ccccc3)c2)cnc1N
Reaction time: 1 h
Yield: 225 %

Procedure:
To a stirred solution of 3-amino-N-methyl-6-(3-{[(pyrrolidin-2-ylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (35.4 mg, 0.01 mmol) and benzaldehyde (24.8 mg, 0.02 mmol) in methanol (3 mL) was added sodium cyanoborohydride (25 mg, 0.04 mmol). The mixture was stirred for 1 h and then acetic acid added until the pH of the solution was 7.0. The solution was stirred for an additional 6 h, solvent was removed and residue was partitioned with CHCl3 and 2 M aqueous sodium hydroxide (5 mL). The aqueous phase was extracted with additional CHCl3 (2×5 mL) and the combined organic layer were washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography provided 10 mg of 3-amino-N-methyl-6-{3-[({[1-(phenylmethyl)pyrrolidin-2-yl]methyl}amino)carbonyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz; CDCl3); 8.7 (s, 1H); 8.65 (s, 1H); 8.28 (br s, 1H); 7.95 (d, 1H); 7.22 (d, 1H); 7.53 (t, 1H); 7.2-7.4 (m, 5H); 4.3-3.5 (m, 7H); 2.95 (d, 3H); 2.35-1.8 (m, 4H); MS (EI) for C25H28N6O2: 445 )
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:31]1([C:37]2[S:41][CH:40]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[NH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:39]1[N:38]=[C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[S:41][C@@H:40]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)C1NN=C(c2ccccc2)S1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (3.1 g) and 1-hydroxybenzotriazole (1.7g) in dichloromethane (100ml) was treated with a solution of the product of step (a) (6.85g) in dichloromethane (25ml). A solution of dicyclohexylcarbodiimide (2.26g) in dichloromethane (20ml) was added over 20 minutes and the mixture was stirred at room temperature for 2 days under nitrogen.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:33])[C:7]([N:9]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:32])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([C:7]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:17]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:18][CH:19]=[C:20]([F:22])[CH:21]=2)=[O:33]
Reactant: COCCOC(=O)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOC(=O)c1c(Cc2ccccc2)c(=O)c2ccc(F)cc2n1-c1ccccc1

Procedure:
To a solution of N-[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-N-phenyl-oxalamic acid 2-methoxy-ethyl ester (500 mg) in MeOH (10 mL) was added K2CO3 (˜150 mg), and the reaction mixture heated at reflux under N2 for 1.5 h. The mixture was then cooled, the salts filtered, and solvent evaporated in vacuo. The residue was chromatographed (0-20% MeOH/DCM) to provide 3-benzyl-7-fluoro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid 2-methoxy-ethyl ester (Compound 130). M+H=432; mp=168.0-169.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](O)=[O:28]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccco1
Product: Cc1ccc(NC(=O)c2ccco2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-furamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-furoic acid using method D. NMR; δH [2H6]—DMSO 10.18,(1H, s), 8.62,(1H, t), 7.93-7.91,(3H, m), 7.69,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.31,(1H, d), 7.27,(1H, d), 6.69,(1H, m), 3.16,(2H, m), 2.19,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.25 min, MH+375.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH2:17][CH3:18])[CH:12]=[C:11](Br)[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:63][CH2:64][CH2:65][N:66]1[CH2:70][CH2:69][CH2:68][CH2:67]1.CC([O-])(C)C.[Na+]>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].O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH2:17][CH3:18])[CH:12]=[C:11]([NH:63][CH2:64][CH2:65][N:66]2[CH2:70][CH2:69][CH2:68][CH2:67]2)[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCC1
Reactant: CCOCc1cc(Br)c(C)c(NCc2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOCc1cc(NCCN2CCCC2)c(C)c(NCc2ccccc2)c1
Temperature: 95 °C
Yield: 58786.8 %

Procedure:
A mixture of benzyl-(3-bromo-5-ethoxymethyl-2-methyl-phenyl)-amine (1.253 g, 3.749 mmol), xantphos (134 mg, 0.232 mmol), 1-(2-aminoethyl)pyrrolidine (0.71 mL, 5.639 mmol), Pd2(dba)3 (10 mg, 0.120 mmol), NaOtBu (658 mg, 6.847 mmol) and anhydrous dioxane (40 mL) was heated to 95° C. for 14 h. The reaction was cooled, filtered through celite, rinsed with EtOAc and concentrated. Chromatography (EtOAc/MeOH) afforded N-benzyl-5-ethoxymethyl-2-methyl-N′-(2-pyrrolidin-1-yl-ethyl)-benzene-1,3-diamine (810 g) as an orange liquid. m/z (M+1) 368.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8][C:7]=2[C:31]=1[CH3:32].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:9]1[C:10]2[C:11](=[O:19])[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[C:18]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:31]([CH3:32])[C:7]=2[N:8]=1
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccncc1-3
Reactant: CN(C)CCN
Solvent: ClCCl
Product: COc1ccc2c3c(c(NCCN(C)C)nc2c1C)C(=O)c1ccncc1-3
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Toluene-4-sulfonic acid 3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (Example 18c-1) (25 mg) was suspended in N,N-dimethylethylenediamine (0.5 ml) and the mixture was stirred at 80° C. for one hour. The mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol=50:1 and dichloromethane-methanol=10:1. The desired product was obtained as a reddish powder (21 mg). ESI−MS: m/z 363 (MH+); 1H-NMR (CDCl3): δ2.36 (6H, s), 2.51 (3H, s), 2.66 (2H, t, J=6.5 Hz), 3.82 (2H, quartet like, J=ca 6.5 Hz), 4.02 (3H, s), 7.12 (1H, d, J=9 Hz,), 7.18 (1H, brt, J=ca 5.5 Hz), 7.54 (1H, dd, J=4.5 Hz, 1 Hz), 8.05 (1H, d, J=9 Hz), 8.80 (1H, d, J=4.5 Hz), 9.27 (1H, d, J=1 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[O:32][CH3:33])[C:21]2=[CH:20][CH:19]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 214e, racemic (2′R,3′R,4′S)-2′-[5-bromo-2-methoxy-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound. MS (H+),
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([C@@H:26]([NH2:28])[CH3:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:28][C@H:26]([C:20]2[C:19]([F:18])=[CH:24][C:23]([F:25])=[CH:22][N:21]=2)[CH3:27])=[N:3][CH:4]=1
Reactant: C[C@H](N)c1ncc(F)cc1F
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cc1F
Temperature: 175 °C
Yield: 80.5 %

Procedure:
A mixture of 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 7; 0.18 g, 0.666 mmol), (S)-1-(3,5-difluoropyridin-2-yl)ethanamine (Method 21; 0.132 g, 0.833 mmol), and DIEA (0.139 ml, 0.800 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 17 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1.5:1) to give the title compound as a white solid (0.21 g, 80%). 1H NMR (400 MHz) δ 12.50 and 12.09 (s, 1H), 9.60 and 8.50 (s, 1H), 8.43 and 8.35 (s, 1H), 7.88-8.04 (m, 3H), 7.26 (br, 1H), 5.33 (m, 1H), 1.88 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 0.94 (m, 1H), 0.86 (m, 1H), 0.74 (m, 1H), 0.62 (m, 1H). MS: Calcd.: 391. Found: [M+H]+ 392.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3].[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]2)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3]
Reactant: OCC1CCNCC1
Reactant: C=CCOc1nc(S(C)(=O)=O)nc(C(=O)OCC)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1nc(N2CCC(CO)CC2)nc(C(=O)OCC)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A solution of ethyl 6-(allyloxy)-5-(benzyloxy)-2-(methylsulfonyl)pyrimidine-4-carboxylate (1.911 g, 4.87 mmol) in THF (40 mL) was stirred with molecular sieves for 30 min. To this mixture was added piperidin-4-ylmethanol (1.683 g, 14.61 mmol) and the resulting mixture was stirred overnight at 70° C. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with water followed by brine then dried (Na2SO4). Filtration followed by concentration gave a yellow oil that was purified by flash column chromatography (Biotage flash chromatography system; 0%-100%, 10 CV) to afford the title compound as a yellow oil (1.2043 g, 58% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42-7.39 (2H, m), 7.35-7.27 (3H, m), 6.10-5.97 (1H, m), 5.42-5.34 (1H, m), 5.28-5.22 (1H, m), 4.91 (2H, s), 4.87-4.84 (2H, m), 4.72-4.63 (2H, m), 4.30 (2H, q, J=7.1 Hz), 3.50 (2H, t, J=5.8 Hz), 2.80 (2H, td, J=12.8, 1.8 Hz), 1.79-1.64 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.23-1.10 (2H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=O)C.C([O-])(O)=O.[Na+].[Br:20]Br.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:20][C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=2)[O:12][CH:13]=1
Reactant: CC(=O)OCc1cc2ccoc2cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCc1cc2c(Br)coc2cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81.4 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethyl acetate (5.17 g, 27.05 mmol) is dissolved in CH2Cl2 (130 mL), layered with saturated NaHCO3 (220 mL), treated with Br2 (8.36 mL, 162.3 mmol) and stirred very slowly for 4.5 h at rt. The mixture is stirred vigorously for 30 min, is diluted with CH2Cl2 (100 mL) and the layers separated. The aqueous layer is extracted with CH2Cl2 (2×100 mL) and the combined organics are concentrated to a small volume under a stream of nitrogen. The solution is diluted with EtOH (200 mL), treated with K2CO3 (22.13 g, 160.1 mmol) and stirred for 2.5 days at rt. The mixture is concentrated to dryness, partitioned between 50% saturated NaCl (200 mL) and CH2Cl2 (5×200 mL), dried over Na2SO4 and concentrated in vacuo to a yellow solid (6.07 g). The crude material is adsorbed onto silica gel (12 g) and chromatographed over 250 g slurry-packed silica gel, eluting with a gradient of 50% EtOAc/hexane to 100% EtOAc. The appropriate fractions are combined and concentrated in vacuo to afford 5.02 g (81%) of (3-bromofuro[2,3-c]pyridin-5-yl)methanol as a white solid. MS (EI) m/z: 227 (M+).