Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=1[CH2:25]Cl>CO>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=1[CH2:25][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: C#CCc1c(C)nc2c(N)cccn12
Solvent: CCN(CC)CC
Solvent: CO
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 38.8 %

Procedure:
To a solution of 8-amino-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (8.0 g) and triethylamine (4.8 g) in methanol (80 ml) was added 2-methyl-6-methoxycarbonylaminobenzyl chloride (10.15 g) and the mixture was stirred at room temperature for 17 hours. After methanol was evaporated in vacuo, the resultant residue was dissolved in methylene chloride (100 ml) and the mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resultant residue was subjected to column chromatography on silica gel (240 g) and eluted with a mixture of chloroform and ethyl acetate (20:1) to give a crystalline product. The crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (6.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.Br.Br[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: Br
Product: CCOC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
216 mg (0.6 mmol) of ethyl {4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate and 228 mg (0.9 mmol) of 3-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 39 mg (14% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:18]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:18])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: N
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 4-chloro-2-fluoro benzoic acid (1.5 g), THF (25 mL), oxalyl chloride (0.5 mL) and ammonia gas to afford 1.45 g of the product. 1H NMR (300 MHz, DMSO d6): δ 7.36 (d, J=6.3 Hz, H), 7.53 (dd, J=8.7 Hz, 1H), 7.64-7.76 (m, 3H).
Reaction SMILES: [C:1](Br)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)CC(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl bromide solution, 5.90 g (45 mmol) of Leucine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl bromide is commenced. Addition of orotoyl bromide continues, with constant cooling and stirring, until all of the orotoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Leucine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/5), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-4-methylpentanoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>CN(C=O)C>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Acetyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(7-(acetamidomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 447.2. found 448.3 (M+1)+. Retention time of 1.76 minutes.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>CC(C)=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: CO[SiH](OC)OC
Solvent: CC(C)=O
Product: CO[Si](CCCOCC1CO1)(OC)OC
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
In a 10-liter flask provided with stirrer, reflux condenser, internal thermometer and 2 dropping funnels, one filled with 2.85 kg of allyl glycidyl ether and the other with 3.05 kg of trimethoxysilane, 500 ml of allyl glycidyl ether or gamm-glycidyloxypropyltrimethoxysilane was heated to 130°C. Then 1 ml of an 0.01 molar solution of the mesityl oxide-platinum dichloride complex in acetone was added and the reaction was allowed to take place with rapid stirring and the simultaneous feeding in of the two reactants, within about 20 minutes. The internal temperature was kept between 130°C and 140°C by slight external cooling and by regulating the feed. This was followed by vacuum distillation producing 5.4 kg of γ-glycidyloxypropyltrimethoxysilane boiling at BP0.05 81°C (nD20 : 1.4290, d420 : 1.073).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: Br
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1Cc1ccccn1

Procedure:
The title compound, MS: m/e=308.1 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: C(OC[C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=O)C.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.C(Cl)C[Cl:50]>>[Cl:50][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Reactant: ClCCCl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2ccccc2O)n1)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Yield: 35 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8b (390 mg, crude from previous reaction), Et3SiH (0.80 mL, 5.0 mmol), and trifluoroacetic acid (1.50 mL, 19.5 mmol ) in dry ClCH2CH2Cl (8 mL ) at 0° C. under nitrogen to give 9b (50.0 mg, 35% for two steps) as a white solid after chromatographic separation on RP C-18 (gradient CH3CN/H2O: 25-30%, containing 1% HOAc). mp 155° C. (dec); IR (KBr) 3600-2800 (br), 3280, 1780, 1661 cm-1 ; 1H NMR (DMSO-d6) δ3.63 (1H, d, J=18.0 Hz), 3.74 (2H, s, CH2), 3.93 (1H, d, J=18.0 Hz), 5.15 (1H, d, J=4.7 Hz), 5.70 (1H, dd, J=8.0 and 4.7 Hz), 6.88 (1H, t, J=7.7 Hz), 6.96 (1H, d, J=7.7 Hz), 7.25 (1H, t, J=7.7 Hz), 7.40 (1H, s), 7.94 (1H, d, J=7.7 Hz), 9.16 (1H, d, J=8.0 Hz, NH), 11.30 (1H, s, OH), 13.80 (1H, br s, CO2H); FDMS m/z 451 (M+, 35Cl), 452 (M+ +1, 35Cl), 453 (M+, 37Cl), 454 (M+ +1, 37Cl); Anal. Calcd for C18H14ClN3O5S2 : C, 47.84; H, 3.12; N, 9.30. Found: C, 48.12; H, 3.16; N, 9.36
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:20][C:21](=[O:22])[CH3:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=CC=Cc1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In a 250 ml single neck flask was charged 13.2 g (100 mmoles,1.0 eq) of cinnamaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 15.7 g of 4-(2-phenylethenyl)-3-buten-2-one as a faintly yellow oil in 91% yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([Li])CCC.IC>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:15])([CH3:16])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cs1
Temperature: -50 °C
Reaction time: 0.67 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.100 g, 0.23 mmol) was dissolved in THF (2.5 mL) and cooled to −78° C. n-Butyllithium (0.12 ml, 0.29 mmol) was added and the reaction was stirred at −50° C. for 40 minutes followed by the addition of iodomethane (0.018 ml, 0.29 mmol). After stirring 40 minutes the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over sodium sulfate to afford the title compound. MS m/z: 457.3 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[N:14][CH:13]([N:29]3C(=O)C4=CC=CC=C4C3=O)[C:12]2=[O:40])=[CH:2]1.O.NN>O1CCCC1>[NH2:29][CH:13]1[N:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH:2]=2)[C:12]1=[O:40]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1csc2ccccc12
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2csc3ccccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of (3RS)-1-(benzothiophen-3-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phtalimido-1H-1,4-benzodiazepin-2-one (0.980 g) in tetrahydrofuran (10 ml) was added dropwise hydrazine monohydrate (0.109 g) under stirring at ambient temperature. The mixture was stirred for 1 hour at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was allowed to stand to ambient temperature. The resultant precipitates were filtered off and washed with tetrahydrofuran. The filtrate and washing were combined and concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel with an eluent of chloroform and methanol to afford (3RS)-3-amino-1-(benzothiophen-3-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][CH2:27][C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1CCCCC1)C2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 40 min. 3-cyclohexyl propionic acid 0.44 ml and WSC 0.59 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 45 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ether. The ether solution was washed with 10% sodium hydroxide solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3(3-cyclohexylpropionyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 20 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hour. The reaction mixture was cooled, then added ether, water and 10% sodium hydroxide solution, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After removing the drying agent, the filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60 230-600 mesh, chloroform-chloroform: acetone=20:1) to obtain the product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(OCC)C.[CH3:15][NH2:16]>O>[CH3:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnccc1Cl
Reactant: CN
Solvent: CCOCC
Solvent: O
Product: CNc1ccncc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Chloronicotinonitrile (45.0 g, 324 mmol) was suspended in water (250 mL) and 41% aqueous methylamine solution (250 mL). The resultant mixture was heated, with stirring, at 90° C. for 1 hour before the mixture was cooled to room temperature and extracted with ethyl acetate (×2). The combined organic layers were washed with water, followed by brine then dried (MgSO4) and evaporated to provide a residue. Trituration of the residue with diethyl ether gave the title compound (40.4 g, 93%) as a white solid. 1H NMR (CDCl3) 2.98 (3H, d, J=5.1 Hz), 5.20 (1H, br s), 6.53 (1H, d, J=6.13 Hz), 8.35 (1H, d, J=6.13 Hz), 8.43 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([OH:53])=[N:44][N:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([O:53][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:44][N:45]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 15.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.976 g), 4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.83 g), potassium carbonate (0.691 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (244 mg, yield 16%) as colorless crystals. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 106-108° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][C:39]1([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C:39]3([CH2:44][OH:45])[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NC1(CO)CCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3(CO)CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (1-amino-cyclopentyl)-methanol according to conditions described in general procedure C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:18][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1ccc(Cl)nn1)c1ccccc1
Temperature: 225 °C
Yield: 5.2 %

Procedure:
To a 5 mL microwave reaction vial was added 3,6-dichloropyridazine (544 mg, 3.7 mmol, 1.0 equiv), cumylamine (500 mg, 3.7 mmol, 1.0 equiv), and DIPEA (640 μL, 3.7 mmol, 1.0 equiv). The reaction was heated in a microwave reactor to 225° C. for 15 min and then diluted with brine (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20% EtOAc/hexanes) to yield 48 mg (5%) of 6-chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine as a white solid.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1>O1CCOCC1>[NH:7]1[C:2](=[O:3])[NH:15][C:13](=[O:14])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]12
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1cccn1N
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2cccn2[nH]1
Temperature: 155 °C
Yield: 63 %

Procedure:
Ethyl chloroformate (4.9 ml, 51 mmole) was added dropwise to a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm, 46.7 mmole, Journal of Heterocyclic Chemistry, 1994, 31, 781) and dry pyridine (4.2 mL, 51 mmole) in dry dioxane (48 mL) under N2 at RT. This was heated at reflux for 1 hr and then the solvent was removed. The residue was heated at 155° C. for 17 hr and then allowed to cool to RT. This was triturated with methanol and the solid was collected by filtration and washed with cold methanol to give the product, 4.43 gm (63% yield): MS: 152 (M+H)+; HPLC Ret Time: 0.36 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C@H:46]([OH:49])[CH2:47][OH:48]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:49][C@H:46]([CH2:47][OH:48])[CH2:45][NH:44][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reaction time: 25 h
Yield: 53.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2.39 mmol) synthesized in Example (97e) was dissolved in methylene chloride (20 mL), and WSCI.HCl (732 mg, 3.82 mmol), (S)-(−)-3-amino-1,2-propanediol (500 mg, 5.49 mmol) and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were added at room temperature, followed by stirring for 25 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired product (666 mg, 54%) as a white solid.