Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: c1cnc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)nc1
Temperature: 180 °C
Yield: 17.7 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol), 2-chloropyrimidine (50 mg, 0.346 mmol) and N,N-diisopropylethylamine (112 μl, 0.629 mmol) in N-methylpyrrolidinone (0.5 ml) was heated at 180° C. in the microwave (Smith Personal Synthesiser) for 600 seconds. The reaction mixture was partitioned between ethyl acetate (10 ml) and saturated NaHCO3 (10 ml). The organic washings were dried over Na2SO4 and concentrated in vacuo to give an oil. The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia, 100:0:0 to 88:12:1.2. Compound still impure so purified further on the Fraction Lynx automated LC system to give the title compound as a solid (22 mg, 17%) 1H NMR (400 MHz, CDCl3) δ 8.30 (brs, 2H), 7.34 (d, 2H), 6.92 (d, 2H), 6.70 (t, 1H), 4.10 (t, 2H), 3.78-3.84 (m, 2H), 3.62-3.72 (multiple peaks, 4H), 3.44-3.55 (m, 2H), 3.40 (m, 2H), 3.04-3.18 (m, 2H), 1.85-2.25 (multiple peaks, 10H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[O:6][C:7]3[C:17]([N:18]=2)=[CH:16][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=3)[CH2:3][CH2:2]1.[Cl:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:19].[CH:1]1([CH2:4][C:5]2[O:6][C:7]3[C:17]([N:18]=2)=[CH:16][C:10]2[CH2:11][CH2:12][N:13]([CH2:20][CH2:21][CH2:22][S:23][C:24]4[N:25]([CH3:40])[C:26]([C:29]5[CH:38]=[CH:37][CH:36]=[C:35]6[C:30]=5[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]6)=[N:27][N:28]=4)[CH2:14][CH2:15][C:9]=2[CH:8]=3)[CH2:2][CH2:3]1
Reactant: c1c2c(cc3oc(CC4CC4)nc13)CCNCC2
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(CC7CC7)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(cyclopropylmethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.19 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a faint yellow slightly hygroscopic solid (0.07 mmol).
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[OH:31][C:25]1[CH:30]=[CH:29][C:28]([CH:8]2[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[S:9]2)=[CH:27][CH:26]=1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: Oc1ccccc1
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(c2ccc(O)cc2)C(=O)N1
Temperature: 50 °C
Reaction time: 35 h
Yield: 23.4 %

Procedure:
Silica gel (Wakogel C-200, 40 mg) was added as catalyst to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.98 g) and phenol (0.51 g) in acetonitrile (20 ml) and the mixture was stirred at 50° C. for 35 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using chloroform-acetonitrile (=5:1) as an eluant. The residue was recrystallized from ethanol to give the titled compound (0.19 g, yield 23.4%) as pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](Cl)=O)=[CH:16]1.N1C=CC(N2C3C=CC=CC=3N=C2/C=C/C2C=CC=CC=2)=CC=1>>[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:16]1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: Nc1ccccc1Nc1ccncc1
Agent: C(=C/c1nc2ccccc2n1-c1ccncc1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccncc1)\c1ccoc1

Procedure:
The titled compound was prepared from N-(4-pyridyl)-o-phenylenediamine and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(4-pyridyl)-2-styryl-1H-benzimidazole (Example 3). MW: 287.32; mp: 171.5-172.5° C.; 1H-NMR (DMSO) δ: 8.88 (2H, dd, J=4.6, 1.7 Hz), 8.07 (1H, br.s), 7.81 (1H, d, J=15.8 Hz), 7.74-7.65 (4H, m), 7.35-7.25 (3H, m), 6.89 (1H, br.s), 6.73 (1H, d, J=15.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1)[C:7](=[O:28])[CH:6]=[N:5]2.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[N:5]=[CH:6][C:7]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CCn2c(=O)cnc3cc(F)ccc32)CC1
Yield: 92.3 %

Procedure:
tert-Butyl {1-[2-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 142, 380 mg, 0.97 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 260 mg (93%) of the crude product as an oil.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].N1C=CC=CC=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([N:4]1[C:5](=[O:6])[C:7]([CH3:8])=[CH:9][NH:1][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of thymine (1) in THF was added pyridine and the reaction was cooled to 0° C. Benzoyl chloride was added carefully at 0° C. and the reaction was stirred overnight at room temperature. The reaction mass was evaporated to give the crude solid which was purified by SiO2 flash chromatography to give the N3-benzoyl thymine (4) as a white solid. NMR (600 MHz, CD3OD): δ 7.94 (m, 2H), 7.71 (t, 1H, J=7.3 Hz), 7.57 (m, 2H), 7.38 (s, 1H), 1.90 (s, 3H); Mass (ESI-MS): 231.22 (M+H); m.p: 178-180° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]2)[CH2:9][CH2:8]1.[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([C:16]2[CH2:15][CH:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH2:19][CH2:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCC(CN2CCN(c3ccccn3)CC2)C1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CC(CN2CCN(c3ccccn3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5.14 g of 3-[[4-(2-pyridinyl)-piperazinyl]methyl]cyclohexanone (Example B) in 250 mL of tetrahydrofuran at 0° C. under nitrogen is added dropwise a solution of phenyllithium (23.5 mL, 2.0M in cyclohexane/diethyl ether, 70/30). The solution is stirred at 0° C. for 1 hour, quenched with dropwise addition of 250 mL of saturated potassium phosphate monobasic solution. The solvent is evaporated in vacuo, the residue is basified with concentrated ammonium hydroxide to a pH of 9 and extracted into chloroform. The chloroform extract is dried over magnesium sulfate and filtered. A solution of the filtrate in 250 mL of chloroform containing 14.5 mL of trifluoroacetic acid is stirred at room temperature under nitrogen for 12 hours. The solvent is evaporated in vacuo, the residue is dissolved into ethyl acetate (250 mL) and washed with 1N sodium hydroxide solution and brine (250 mL of each). The ethyl acetate extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography (silica gel, 90% hexanes - 10% ethyl acetate) to give (±)-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4) as an off-white solid; mp 96°-98° C. and (±)-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4a) as an off-white solid; mp 78°-82° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[CH:22]2)=[CH:11][C:10]=1[NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:33][C:18]([NH:17][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH:11]=1)[OH:34])([CH3:32])[CH2:19][CH2:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[CH:22]1
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
0.10 g palladium (5% on activated charcoal) were added to. a solution of 0.30 g (0.41 mmol) (R)—N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl)phenyl)-benzenesulphonamide in 15 mL ethanol. The reaction mixture was shaken in an autoclave under a hydrogen pressure of 20 psi at ambient temperature for 3 h. The hydrogen pressure was released, the palladium was filtered off and the filtrate was freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%) (R)—N-(5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-2-hydroxy-phenyl)-benzenesulphonamide was obtained as a colourless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (730 mg, 1.44 mmol) was initially charged in dry THF (35 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 687 mg, 2.88 mmol; 2 eq.) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. Water (20 ml) was then added, the reaction mixture was concentrated and the residue was taken up in ethyl acetate (200 ml). The organic phase was washed with saturated sodium chloride solution (3×30 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:1). The title compound was obtained as a colorless solid (700 mg, 99% of theory).
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([C:8]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[CH2:5][CH:6]=O.[CH3:26][NH2:27].[BH4-].[Na+].O>CO.CO.CCOC(C)=O>[CH3:26][N:27]1[CH2:6][CH2:5][CH:4]([C:8]2[N:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:3]1=[O:25]
Reactant: CN
Reactant: COC(=O)C(CC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCN(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a magnetically stirred solution of 2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-4-oxo-butyric acid methyl ester 36b (0.035 g, 0.0988 mmol) in methanol (1 mL) at room temperature under Ar atmosphere was added a 40% aqueous solution of methyl amine (0.009 mL, 0.0988 mmol). The reaction mixture was stirred for 1 h at room temperature. NaBH4 (0.0074 g, 0.197 mmol) was added at room temperature. After 30 min, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent), which gave the title compound (0.006 g, 19%) as a white solid. (400 MHz, CDCl3) 2.31 (s, 3H), 2.33 (m, 2H), 2.39 (s, 3H), 3.00 (s, 3H), 3.51 (m, 2H), 4.41 (t, J=10.2 Hz, 1H), 7.02 (dd, J=1.1, 9.1 Hz, 1H), 7.24 (d, J=7.7 Hz, 2H), 7.25 (s, 1H), 7.53 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N=C=N.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([Br:50])[C:34]1=[O:51].CN=C=O>CN(C)C=O.O1CCCC1>[Br:50][C:35]1[C:34](=[O:51])[N:33]([CH2:32][C:31]2[CH:30]=[C:29]([CH:54]=[CH:53][CH:52]=2)[CH2:28][NH:27][C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:38]([CH3:39])=[CH:37][C:36]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CN)c1
Reactant: COCC(=O)O
Agent: CN=C=O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCC(=O)NCc1cccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added methoxyacetic acid (0.09 g, 1.00 mmol) A stock solution of 1-hydroxybenzotriazole (3 mL, 0.16 M) and N-methylmorpholine (3 mL, 0.43 M) in N,N-dimethylformamide were added to the reaction vessel followed by approximately 0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (3 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. 1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (EXAMPLE 161) (0.30 g, 0.668 mmol) was then added to the reaction vessel followed by additional N,N-dimethylformamide (5.0 mL) and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.06 g of polyamine resin (2.63 mmol/g) and approximately 2.67 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) afforded a tan solid (0.321 g, 89.4%). 1H NMR (400 MHz, DMF-d6) δ 8.33 (br s, 1H), 7.81 (app q, J=7.85 Hz, 1H), 7.40-7.23 (m, 5H), 7.09 (d, J=7.25 Hz, 1H), 6.68 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, J=6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m/z 521.0891 (M+H C24H23BrF2N2O4 requires 521.0882).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[N:1]1([CH2:11][C:13]2[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:17]([CH:27]=2)[C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Morpholine (26 uL, 0.30 mmol) and acetic acid (17 ul, 0.30 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.301 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50° C. then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight. Saturated NaHCO3 solution (5 ml) was added and the mixture stirred for 5 minutes. The organic layer was then diluted with dichloromethane (5 ml) before being separated and dried (MgSO4). The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound. 40 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.[CH3:27][C:28]1([O:31][CH2:30]1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[N:12]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC(C)(C)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 40 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (102.7 mg, 0.279 mmol) in 3 mL, DMF was added isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (180.0 mg, 0.5524 mmol). The reaction was stirred at 40° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 49.3 mg (40%) of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=441.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.32 (dd, 1H), 8.76 (d, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 7.48 (dd, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.28 (t, 1H), 4.72 (s, 1H), 4.07 (s, 2H), 3.84 (s, 3H), 1.12 (s, 6H).
Reaction SMILES: [Na].CO.[ClH:4].[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[N:14]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH:13]=1)=[O:11]>COCCOC>[ClH:9].[ClH:4].[NH:7]([C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[N:14]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: COc1ccc2c(C(=O)Cl)cn(-c3ccnc4ccccc34)c2c1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc2c(C(=O)NC(=N)N)cn(-c3ccnc4ccccc34)c2c1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
0.87 g (38 mmol) of sodium is added at a temperature in the region of 22° C. under an argon atmosphere to 60 cm3 of methanol. After complete dissolution, 3.6 g (37.5 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 22° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 60 cm3 of 1,2-dimethoxyethane. 2.4 g (7.13 mmol) of 3-chlorocarbonyl-6-methoxy-1-(quinol-4-yl)-1H-indole are subsequently added at a temperature in the region of 22° C. under an argon atmosphere. After stirring at reflux for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 cm3 of water. The suspension is filtered and dried to give a beige-coloured powder which is purified by silica gel chromatography [eluent: dichloromethane/methanol (85/15 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.7 g of a beige-coloured foam are obtained, which foam is triturated in 60 cm3 of N hydrochloric acid to provide, after filtration, 1.86 g of 3-guanidinocarbonyl-6-methoxy-1-(quinol-4-yl)-1H-indole dihydrochloride in the form of yellow crystals melting at a temperature of greater than 260° C. Mass spectrum (EI): m/e 359 (M+·), m/e 301. IR spectrum (KBr): 3356, 2587, 1694, 1630, 1595, 1542, 1495, 1441, 1261, 1232, 1192, 823 and 763 cm−1.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][NH:21][CH2:22]2)[CH2:17]1)=[O:15].Cl[C:31]1[CH:40]=[N:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][N:21]([C:31]3[CH:40]=[N:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:22]2)[CH2:17]1)=[O:15]
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CCN(c3cnc4ccccc4n3)CC21
Temperature: 80 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A mixture of trifluoro acetic acid salt of biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone (Intermediate 3, 122.0 mg, 0.3 mmol), 2-chloro quinoxaline (60.0 mg, 0.36 mmol), K2CO3 (166 mg, 4 mmol) in DMF (7 mL) was stirred at 80° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (120 mL). The organic layers were washed with water (2×30 mL), combined, dried (Na2SO4), filtered and concentrated. The crude residue was purified on HPLC (basic system) to yield the title compound (51 mg, 40%). MS (ESI) mass calcd. for C27H24N4O, 420.51; m/z found, 421 [M+H]+. 1H NMR (CDCl3): 8.44 (s, 0.55H), 8.17 (s, 0.45H), 7.97-7.87 (m, 1H), 7.76-7.71 (m, 0.5H), 7.65-7.50 (m, 2H), 7.48-7.30 (m, 7H), 7.09-6.94 (m, 2H), 7.20-7.12 (m, 0.5H), 4.78-4.49 (m, 1H), 4.02-3.78 (m, 1H), 3.76-3.58 (m, 2H), 3.55-3.48 (m, 0.5H), 3.32-3.23 (m, 0.5H), 3.15-2.97 (m, 1H), 2.74-2.39 (m, 1H), 2.12-1.54 (m, 3H).