Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)[CH3:16].[CH2:28]([O:30][C:31](=[O:36])/[CH:32]=[C:33](\[NH2:35])/[CH3:34])[CH3:29]>C(O)C>[CH2:28]([O:30][C:31]([C:32]1[CH:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:27])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:35][C:33]=1[CH3:34])=[O:36])[CH3:29]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cc(OC)c(OC)c(OC)c2)C(C(=O)OCC)=C(C)N1
Yield: 40 %

Procedure:
11.8 g of 3,4,5-trimethoxybenzaldehyde, 14 g of oxalacetic acid diethyl ester and 7.8 g of β-aminocrotonic acid ethyl ester in 30 ccs of ethanol are heated to the boil overnight and light yellow crystals of melting point 134° are obtained. Yield 40%.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:21][CH2:22][NH:23][CH3:24])=[C:4]1[CH3:25].C=O.[C:28]([BH3-])#N.[Na+]>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:21][CH2:22][N:23]([CH3:28])[CH3:24])=[C:4]1[CH3:25]
Reactant: CNCCc1c(C)n(C)c2ccc(S(=O)(=O)c3ccccc3)cc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(CCN(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 24.7 %

Procedure:
A solution of 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine hydrochloride (0.34 g, 0.91 mmol) and formaldehyde (37%, 1.4 mL, 18.80 mmol) in acetonitrile was treated with sodium cyanoborohydride (0.92 g, 14.69 mmol) in portions. The reaction was stirred at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the residue partitioned between CHCl3 and NH4OH. The layers were separated and the aqueous layer was extracted with CHCl3. The organic layers were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 75% EtOAc/hexane) to give 0.08 g (23%) of white solid as the title compound: mp 169.6-171.9° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.93-7.91 (m, 2H), 7.63-7.55 (m, 5H), 3.67 (s, 3H), 2.86-2.82 (m, 2H), 2.41-2.37 (m, 2H), 2.36 (s, 3H), 2.24 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 142.8, 137.9, 136.8, 132.7, 130.3, 129.3, 126.8, 126.7, 118.7, 118.0, 110.2, 110.0, 59.9, 44.9, 29.7, 21.8, 9.9; IR (diffuse reflectance) 2936, 2776, 2760, 1482, 1449, 1377, 1303, 1285, 1153, 1143, 1094, 729 (s), 687, 651, 619 cm−1; HRMS (FAB) calcd for C20H24N2O2S+H 357.1637, found 357.1649; Anal. Calcd for C20H24N2O2S: C, 65.72; H, 6.88; N, 7.66. Found: C, 65.52; H, 6.71; N, 7.73.
Reaction SMILES: C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1)[CH3:8])(=O)CCC.[C:21]([O:27][CH:28]=[CH2:29])(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:17][CH:16]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:6])[CH3:8])=[CH:14][CH:13]=1.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)OC(C)c1ccc(OC(C)OCC)cc1
Reactant: C=COC(=O)CCCC
Product: CC(O)c1ccc(OC2CCCCO2)cc1
Product: CCCCC(=O)OCC
Yield: 94 %
Yield: 91 %

Procedure:
The procedure of Example 5 (i) was repeated except that vinyl valerate was used instead of 2,2,2-trichloroethyl butyrate to give 10.4 g of S-form of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethanol (yield: 94%) and 13.9 g of R-form of 1-(4-tetrahydro-2-pyranyloxy)phenyl)ethyl valerate (yield: 91%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1.[K+].[Br-]>O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH2:33][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(4-chlorobenzyl)piperazine, yield 86% White crystals, m.p. 232-234° C.; 1H NMR (DMSO-d6): δ11.92 (br s, 1H), 3 AB-systems: 7.83-7.62 (t-like, 4H) and 7.62-7.48 (d-like, 2H), and 7.32-7.07 (m, 6H); 4.51-3.95 (br s at 4.37 ppm overlapping with br signal at 4.2 ppm, 4H), 3.95-2.95 (br m, 9H: 6H+water); IR (KBr): ν 1717 (C═O) cm−1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:30][C:31]1[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:37]([C:33]3[S:32][C:31]([CH3:30])=[N:35][C:34]=3[CH3:36])=[O:38])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3sc(C)nc3C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
65 mg (0.15 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 21 mg (0.13 mmol, 0.9 eq.) of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid were reacted according to General Method 1. Yield: 43 mg (73% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]=O)[CH:5]=[N:4]1)[CH3:2].Cl.Cl.[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[CH2:21][CH2:22][N:23]([CH2:9][C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=3[CH3:8])[CH2:24][CH2:25]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CCn1ncc(C=O)c1C
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
Yield: 88.6 %

Procedure:
Dissolve 1-ethyl-5-methyl-1H-pyrazole-4-carbaldehyde (2.92 g, 21.1 mmol) in 1,2-dichloroethane (184 mL). Add 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (4.97 g, 18.3 mmol), triethylamine (5.9 mL, 42.3 mmol), sodium triacetoxyborohydride (6.72 g, 31.7 mmol) and acetic acid (1.98 mL) and stir at room temperature for 18 hr. Add aq. saturated sodium bicarbonate and extract four times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate) to give 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (5.2 g, 88%). MS (ES): m/z=321 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:36][CH2:35]1
Reactant: Fc1ccc(N2CCCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCCN(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenyl)-1,4-diazepane (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as eluent to give 7-(2-(4-(2,4-difluorophenyl)-1,4-diazepan-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=479.01). 1H NMR (DMSO-d6, 400 MHz) δ 1.82 (m, 2H), 2.71 (m, 2H), 2.82 (m, 2H), 2.88 (t, 2H, J=6.4 Hz), 3.24 (m, 4H), 4.22 (t, 2H, J=6.4 Hz), 6.57 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 6.85-6.94 (m, 2H), 7.09 (m, 1H), 7.14 (d, 1H, J=3.6 Hz), 7.19 (d, 1H, J=3.2 Hz), 7.51 (br s, 2H, NH2), 7.92 (s, 1H).
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[S:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].C1(SC)C=CC=CC=1>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][NH2:8])=[S:18])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: NNC(=S)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (1.97 mmol) in CH2Cl2 is added trifluoroacetic acid (3 mL) and thioanisole (2.7 mmol). The mixture is stirred at room temperature for 1 hour. After evaporation of the solvent the mixture is purified by automated column chromatography (hexanes/EtOAc) to yield 4-fluoro-thiobenzoic acid hydrazide trifluoroacetic acid salt: 1H NMR (400 MHz, CDCl3) δ 9.5 (bs, 3H), 7.8-7.76 (m, 2H), 7.05 (t, J=8.4 Hz, 2H); LC/MS: (ES+) 171 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7]OC[CH2:4]1.[C:8]1([CH:14]=[CH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(I)(C)C>CN(P(N(C)C)(N(C)C)=O)C>[CH:3]([CH:16]([CH:15]=[CH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:7])[CH3:4]
Reactant: CCOC(=O)CC=Cc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)I
Product: CCOC(=O)C(C=Cc1ccccc1)C(C)C

Procedure:
To sodium hydride (2.84 g, 57% in oil, washed with pentane), 110 ml dry THF and 20 ml HMPT, cooled to 0° and under nitrogen, is added 12.7 g ethyl 4-phenyl-3-butenoate slowly with stirring. Then 6.5 ml of isopropyliodide is added and the reaction mixture is stirred for about 60 hrs. The reaction is worked up by extracting into water/ether mixture. The aqueous phase is extracted with ether. The organic phases are combined, washed with brine, dried over calcium sulfate and rotoevaporated to give ethyl 2-isopropyl-4-phenyl-3-butenoate, which is hydrolyzed (potassium hydroxide, water-methanol) to the acid, 2-isopropyl-4-phenyl-3-butenoic acid. The acid is reacted with m-phenoxybenzyl alcohol following the procedure of Example 4 to yield m-phenoxybenzyl ester of 2-isopropyl-4-phenyl-3-butenoic acid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[C:21]([N:30]2[CH2:33][CH:32]([NH2:34])[CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:20]1[C:21]([N:30]2[CH2:31][CH:32]([NH:34][C:2]3[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:33]2)=[N:22][CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C(NC2CN(c3ncc(C(F)(F)F)cc3Cl)C2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 84796.1 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-amine (133 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturate aqueous NaHCO3, dried with Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (223 g, 84.0%). 1H NMR (500 MHz, CDCl3): δ 1.60 (d, 6H), 4.01-4.06 (m, 3H), 4.10-4.15 (m, 2H), 4.40-4.48 (m, 1H), 5.62 (bs, 1H), 7.51 (s, 5H), 7.59 (s, 1H), 8.25 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 20.38, 44.61, 48.06, 59.87, 109.52, 115.56, 117.98 (q, JC-F=33.6 Hz), 124.42, 124.75, 129.29, 130.48, 131.49, 134.49, 135.16, 143.70, 156.92, 158.26; Mass Spectrum: M+H+ 501.1.
Reaction SMILES: [C:1]([NH:20][NH2:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22]([OH:41])(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].ON1C2C=CC=C[C:46]=2N=N1.C(N=C=NC(C)C)(C)C>O1CCCC1>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:20][NH:21][C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:46])=[O:41])=[O:19]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)NN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(=O)NNC(=O)CCCCCCCCCCCCCCCCC
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 20.0 g of stearic hydrazide, 21.0 g of stearic acid, 10.3 g of 1-hydroxybenzotriazole in 205.0 g of tetrahydrofuran was added 9.3 g of diisopropylcarbodiimide dropwise at room temperature, and the mixture was stirred for 3 hours under reflux. The deposited crystal was filtrated, and re-crystallized from isopropyl alcohol, to obtain 23.9 g of the intended compound.
Reaction SMILES: [NH:1]([CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)N.C(OCC)(=O)C.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH2:1][CH2:3][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: [H][H]
Reactant: NNCC1(O)c2ccccc2CCc2ccccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NCC1(O)c2ccccc2CCc2ccccc21

Procedure:
A mixture of 8 g. of freshly prepared 5-hydrazinomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol, 40 mg. of platinum dioxide, 120 ml. of ethyl acetate and 40 ml. glacial acetic acid is hydrogenated at room temperature and about atmospheric pressure until the uptake of hydrogen is about stoichiometric. The resulting mixture is filtered, evaporated in vacuo and the residue taken up in 400 ml. of chloroform, made neutral by shaking with 10% sodium bicarbonate solution, and the aqueous phase discarded. The organic phase is extracted twice with water and then with saturated sodium chloride solution, followed by drying and evaporation in vacuo to about 50 ml. to effect crystallization which is completed by adding 50 ml. of diethyl ether to obtain 5-aminomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol, m.p. 147°-149° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCc1ccc(Br)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COCc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromophenyl)methanol (1.0 g, 5.35 mmol) in DCM (25 mL) cooled in an ice bath was added rhodium(II) acetate dimmer (0.236 g, 0.535 mmol). To the resulting mixture was slowly added a solution of ethyl diazoacetate (0.721 mL, 6.95 mmol) in DCM (1 mL). The reaction mixture was stirred for 0.5 h. Additional ethyl diazoacetate (300 μL) was added and the resulting mixture was stirred for an additional 0.5 h. The mixture was concentrated and the residue was purified by chromatography (0, 5, 10, 15% EtOAc/Hexanes) to give the title compound. LCMS m/z=273.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.1 Hz, 3H), 4.12-4.15 (m, 2H), 4.16 (s, 2H), 4.52 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3ccccc3)cc2)=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-methyl-3-(4-phenoxyphenyl)pyrazin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 89.0 mg) and 2-chloroethanesulfonyl chloride (0.140 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc then recrystallized from EtOAc-EtOH to give the title compound (86.0 mg) as a white solid.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5])#[N:2]
Reactant: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To a 25 ml one necked round bottom flask 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide (0.1 g, 0.000182 mole) was taken in CH2Cl2 (10 ml). To this reaction mixture TFA (2.0 ml) was added dropwise at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and then stirred for 16 hrs. After completion of the reaction, CH2Cl2 was distilled out and set pH 8 to 9 using saturated NaHCO3 solution (20.0 ml) at 5° C. Reaction mixture was stirred for 15 min. The solid was filtered, washed with methanol followed by n-pentane and dried under vacuum to yield 40 mg of 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[F:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[S:40]([CH2:39][C:36]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:50][CH3:51])[C:29]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)=[CH:38][CH:37]=1)(=[O:42])=[O:41]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(2-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 100) and furan-3-yl boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC2CCOCC2)s1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) in DMF (1.2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.00 mmol) and 4-aminotetrahydropyran (22 mg, 0.22 mmol). The resulting reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 4:1 to 0:1) afforded the title compound (64 mg, 77%) as a white solid after recrystallization from ethyl acetate:heptane. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [Mg].II.BrC(Br)C.[CH:8]([C:11]1[CH:12]=[C:13](Br)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9].[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:8]([C:11]1[CH:12]=[C:13]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9]
Reactant: O=C1CCCCC1
Reactant: CC(C)c1cccc(Br)c1
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2(O)CCCCC2)c1
Temperature: 70 °C
Yield: 63.2 %

Procedure:
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF is added a small crystal of iodine followed by 40 μL of dibromoethane. This mixture is placed in a water bath at 50° C. and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry tetrahydrofuran (THF) is added dropwise over 20 min, while the bath temperature is raised to 70° C. The mixture is stirred and refluxed for 40 additional min. The solution is cooled in an ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry THF is added dropwise over 15 min. The ice bath is removed and the mixture is allowed to warm to ambient temperature over 1 h. The solution is decanted into aqueous saturated NH4Cl, and combined with an ether wash of the residual magnesium turnings. The organic phase is washed twice more with aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated. Chromatography on silica gel, eluting with 10% ethyl acetate in heptane, affords 2.7 g (12 mmol, 60%) of compound 1 as an oil: 1H NMR (CDCl3) δ 7.39 (m, 1H), 7.3 (m, 2H), 7.12 (m, 1H), 2.92 (m, 1H), 1.84–1.54 (m, 10H), 1.26 (d, J=7 Hz, 6H).