Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (6 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.53 g) and DBU (0.27 g) was refluxed for an hour and the resulting precipitate was collected by filtration to give the title compound (0.72 g) as pale yellowish powder, mp 229°-230° C. Analysis (%) for C23H27F2N3O5, Calcd. (Found): C, 59.60 (59.47); H, 5.87 (5.85); N, 9.07 (9.01).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CO)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
2-(3-Nitrophenyl)propanal (7.531 g) was dissolved in ethanol (100 ml), to which was then added sodium borohydride (1.9 g) under ice-cooling, followed by stirring at room temperature for one hour. Brine was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent was purified by silica gel column, to give the title compound (6.275 g, 57.19% in 3 steps) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc(OC)c2sc(-c3ccc([N+](=O)[O-])cc3)nc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c2sc(-c3ccc(N)cc3)nc2c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene add lawessons reagent (4.6 g, 11.5 mmol) and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,4,5-trimethoxybenzaldehyde (22f, 137 mg, 1 eq) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6f as a yellow solid (53%).
Reaction SMILES: Br.[N+:2]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][NH:6]1)([O-:4])=[O:3]>CC(O)=O>[N+:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])C1NC=Cc2ccccc21
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1nccc2ccccc12
Temperature: 25 °C
Yield: 28.5 %

Procedure:
Hydrobromic acid (3.0 M in HOAc, 1 mL) was added to a suspension of the dihydronitroisoquinoline (0.83 g) in glacial HOAc (2 mL). The mixture was heated to 100° C for 1 day with occasional addition of more hydrobromic acid solution (3 mL overall). After the reaction, the mixture was allowed to cool to room temperature, concentrated in vacuo, diluted by water, and extracted twice with ethyl ether. Combined organics were washed by saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed on silica gel (5% to 10% ethyl acetate in hexane) to give 234 mg of nitroisoquinoline (35%) as solids, along with 95 mg of 4-bromo-1(2,4,6-trimethylphenyl)isoquinoline (13%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:20]([C:19]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:18]=2[F:17])=[N:16][N:15]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cc(F)c(F)cc2F)o1
Yield: 46 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (4.18 g, 19.2 mmol) was converted using 2,4,5-trifluorobenzoic acid instead of o-toluic acid to the title compound (3.16 g, 46%) which was obtained as a white solid. MS: m/e=358.1 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:12]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:15]1[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)([O-:18])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 125.6 %

Procedure:
To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene (6.63 ml) was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.335 g, 1.492 mmol) followed by ethanol (3.31 ml) and 2 M aqueous potassium carbonate (1.492 ml, 2.98 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.086 g, 0.075 mmol) and the flask was heated at 110° C. under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude product was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to give 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine (499 mg, 1.874 mmol, 80%) as a yellow solid: mp 144.0-146.0° C.; 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.82-7.74 (m, 2H), 7.55-7.48 (m, 4H); EIMS m/z 266.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1.OS([O-])=O.[Na+]>ClCCl.C(#N)C>[Br:27][C:17]1[CH:18]=[C:13]([O:12][C@H:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 82.5 %

Procedure:
(S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (12 g, 39.87 mmol) was dissolved in dichloromethane (15 mL), a solution of N-bromosuccimide (7.1 g, 39.87 m mol) in acetonitrile (20 mL) was added dropwise slowly under the cooling of ice bath, and the reaction was stirred. After TLC test has showed that reaction was completed, a small amount of NaHSO3 solution was added to quench it, and the pH was adjusted to about 8-9 using sodium carbonate solution. The mixed solution was concentrated under reduced pressure to remove dichloromethane and acetonitrile. The residue was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated; the residue was purified via silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to yield the target product as yellow solid (12.5 g, yield: 83%).
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydropen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-d6) δ11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][OH:19])=[O:17])=[O:9])=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(Cl)Cl>[C:4]1([NH:7][C:8](=[O:9])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][O:19][C:30](=[O:32])[CH3:31])=[O:17])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Reactant: CC(=O)OC(C)=O
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)ONC(=O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of SAHA (0.43 g, 16.3 mmol) in pyridine/CH2Cl2 (5/5 mL) was added acetic anhydride 1-hydroxybenzotriazole (153 μL, 16.3 mmol). After stirring for 18 h at RT, the solvent was removed, and the material was without further purification. 1H NMR (DMSO-d6) δ 11.71 (br s, 1H), 10.01 (br s, 1H), 7.75 (d, J=7.6 Hz, 2H), 7.44 (dd, J=7.6, 7.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.35-2.20 (m, 2H), 2.30 (s, 3H), 1.82-1.58 (m, 4H), 1.58-1.36 (m, 4H). MS (EI): cal'd (MH+) 307.1, exp (MH+) 307.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[NH:12][C:10]3[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[NH:1]2)=[CH:17][CH:16]=1
Reactant: Nc1cccc2cccc(N)c12
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CN(C)c1ccc(C2Nc3cccc4cccc(c34)N2)cc1
Yield: 65.7 %

Procedure:
A solution of 3.2 g (0.02 mole) of 1,8-diaminonaphthalene and 3.0 g (0.02 mole) of p-dimethylaminobenzaldehyde in 35 ml of ethanol was refluxed for 2 hours. After cooling, the resulting precipitate was filtered and recrystallized from ethanol. There were obtained 3.8 g of 2-(p-dimethylaminophenyl)-2,3-dihydroperimidine as colorless crystals, m.p. 165°-166° C. (Compound No. 18).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:28]5[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccncc1
Yield: 78.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and pyridine-4-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (163 mg, yield 78%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:35])[C:30]1[O:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:34]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:29][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCc1ccco1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCc3ccco3)ccc21
Yield: 90.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide (108 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), furfurylamine (26 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 489.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.92 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.57 (s, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 6.39 (dd, 1H), 6.27 (d, 1H), 4.48 (d, 2H), 3.62 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[F:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[F:25][C:26]1[C:27]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(F)cn1

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (5-fluoro-2-methoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.15 (qd, J=12.3, 4.4 Hz, 2H) 1.55 (d, J=12.9 Hz, 2H) 1.74 (ddt, J=11.1, 7.4, 3.9, 3.9 Hz, 1H) 3.13 (t, J=6.3 Hz, 2H) 3.74-3.82 (m, 5H) 7.74 (d, J=4.8 Hz, 1H) 8.03 (d, J=3.0 Hz, 1H) 8.16 (d, J=2.5 Hz, 1H 8.30-8.45 (m, 2H) 8.66 (t, J=5.7 Hz, 1H) 8.84 (d, J=1.3 Hz, 1H). MS m/z [M+H]+ 428.5.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl.CO>[Br:1][CH2:18][C:17]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CBr)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of bromine (4.3 ml) in chloroform (20 ml) was added dropwise over 30 minutes at 10°-15° C. to a stirred solution of 1-[1-(2-naphthyl)cyclobutyl]-ethanone (20 g) in a mixture of methanol (20 ml) and chloroform (30 ml). The mixture was then stirred at ambient temperature for 1.5 hours, poured onto ice-water (300 ml) and the product extracted into dichloromethane (3×150 ml). The extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then water, dried over calcium chloride and the solvent removed in vacuo to give 2-bromo-1-[1-(2-naphthyl)cyclobutyl]-ethanone as an oil (24.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:27]C(=O)OC(C)(C)C)[CH2:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22]C(=O)C4)[CH:14]=[N:13]2)=[CH:4][CH:3]=1.[C:35]([OH:41])(C(F)(F)F)=[O:36]>C(Cl)Cl>[NH2:27][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:35](=[O:36])[O:41][C:19]=3[CH:18]=2)[CH:14]=[N:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](CCn1cc(-c2ccc3c(c2)CC(=O)N3)cn1)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: N[C@H](CCn1cc(-c2ccc3[nH]c(=O)oc3c2)cn1)Cc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
tert-Butyl(S)-1-(4-chlorophenyl)-4-(4-(2-oxoindolin-5-yl)-1H-pyrazol-1-yl)butan-2-ylcarbamate was dissolved in DCM (2 mL), TFA (2 mL, 26 mmol) was added, and the mixture was stirred for 2 hours. The mixture was concentrated by vacuum distillation and partially purified with reverse-phase HPLC (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O 0.1% TFA, 10.5 minute gradient). After concentrating the sample by vacuum distillation, the residue was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. After washing with MeOH, the desired compound was eluted with 2M NH3 in MeOH. The residue was partially purified using column chromatography (2M NH3 in MeOH/DCM 0-5%). The residue was purified SFC chromatography (Princeton Chromatography Pyridine column 21×250 mm, 5 um, 65 mL/min, 40° C., outlet pressure 100 bar, 220 nm, 10-50% MeOH 2% DEA/CO2, 5 minute gradient) to give a tan film (7.1 mg, 4%). HRMS (TOF) Calcd for C20H20ClN4O2+: 383.1269, found: 383.1268.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13](I)[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.O>[NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under protective argon gas a mixture of 235 mg (0.64 mmol) ethyl (R)-2-amino-3-(4-amino-3-chloro-5-iodo-phenyl)-propionate, 45.9 mg (0.064 mmol) bis-(triphenylphosphine)-palladium(II)-dichloride, 6.0 mg (0.032 mmol) copper(I)- iodide and 15 ml triethylamine was combined with 0.19 ml (1.32 mmol) trimethylsilylacetylene and stirred for 3 hours at ambient temperature. The reaction mixture was combined with 30 ml of water and extracted with 40 ml of ethyl acetate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and the residue was purified by column chromatography through silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(Cl)cc2ncnn12
Product: Clc1cc2ncnn2c(Cl)n1

Procedure:
The mixture of 7-Chloro-[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (35 mg) in POCl3 was heated at reflux for 3 hours. After removal of the volatiles, the residue was purified by a short plug column eluting with 1:1 EtOAc/hexane to give 5,7-Dichloro-[1,2,4]triazolo[1,5-c]pyrimidine as an off-white solid (11 mg). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H) 7.72 (s, 1H). [M+H] calc'd for C5H2Cl2N4, 189; found, 189.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:9][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([O:11][CH3:10])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2nc(=O)[nH]cc2F)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
12.9 g of 5-fluorocytosine was suspended in 78 ml of pyridine, followed by addition of 23.1 g of 3,4,5-trimethoxybenzoyl chloride and stirring at 100° C. for 5 hours. The reaction mixture was cooled down to room temperature and then poured into 310 ml of water at room temperature over a period of 20 minutes. The precipitated crystals were collected by filtration to obtain 29.2 g (90.4%) of 5-fluro-N4 -(3,4,5-trimethoxybenzoyl)cytosine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH2:12][N:13]=[C:14]4[C:19]=3[CH:18]=[C:17]([F:20])[CH:16]=[CH:15]4)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].C(O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Fc1ccc2c(c1)=C(C1=CCC3(CC1)OCCO3)CN=2
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A mixture of of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-fluoro-2H-indole (8.5 g) and 10% palladium on carbon (2.72 g) in ethanol (200 ml) was hydrogenated for 5 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (methanol-methylene chloride) afforded 7.55 g (82%) of product as a white solid: mp 183-185° C.