Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C([Li])CCC.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)OCC1>C1COCC1.CCCCCC>[OH:22][C:19]1([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21][C:16](=[O:12])[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1cocn1
Agent: B
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ncco2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1,3-oxazole (2.0 mL, 30.41 mmol) in THF (20 mL) was added 1.0 M solution of borane in THF (30.4 mL) at room temperature. The mixture was stirred for 1 hour before being cooled down to −78° C. To the above solution was added a 1.6 M solution of n-butyllithium in hexane (19 mL). After stirring at −78° C. for one hour, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.22 g, 33.45 mmol) in THF (10 mL) was added. After being stirred at −78° C. for 5 hours, the reaction was quenched by addition of a 3 M solution of HCl in water (40 mL). The resulting solution was stirred at room temperature overnight, neutralized with potassium carbonate and extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. Purification by flash chromatography on silica eluting with EtOAc afforded the desired product (3.9 g, 70%). LC-MS calculated for C9H11NO3: (M+H)+182; found 182.0.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C([BH3-])#N.[Na+].[CH:35](=O)[CH3:36].C(O)(=O)C>CO.O1CCCC1>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH2:35][CH3:36])[CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2NC)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(C)CC)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To 1.5 g (3.6 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-methylamino-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 434) dissolved in 10 ml of methanol and 5 ml of tetrahydrofuran was added 0.15 g (2.4 mmole) of sodium cyanoborohydride and 0.2 g (4.3 mmole) of acetaldehyde. To this stirred solution was dropwise added 0.6 g (9.5 mmole) of acetic acid dissolved in 3 ml of methanol. After 30 minutes, the reaction was concentrated in vacuo, dissolved in 50 ml of diethyl ether, washed with water, washed with 1M aqueous sodium hydroxide, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Trituration with diethyl ether and hexanes yielded 1.4 g of the desired compound, mp 130°-132° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])(=[O:3])[CH3:2].S(Cl)(Cl)(=O)=O.CC1C=C(C)C=C(C)N=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCC1CCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)OCCCCCC1=CCCC1=O

Procedure:
161 g [0.76 mol ] of 2-(5-acetoxypentyl)-cyclopentanone were dissolved in 440 ml of carbon tetrachloride, and a solution of 76 ml [0.935 mol] of sulfuryl chloride in 75 ml of carbon tetrachloride was added dropwise, while stirring at 10°-15° C., and the whole was stirred for 4 hours at room temperature. The solvent was distilled off under reduced pressure, the residue dissolved in toluene, washed with water and bicarbonate solution and dried over magnesium sulfate. 150 ml [1.25 mols] of 2,4,6-trimethylpyridine were added to the filtered solution, which was then refluxed, while stirring, for 15 hours. After cooling, the solution was washed twice with 2 n HCl, once with water and once with sodium bicarbonate solution, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was distilled under a reduced pressure of 0.5 mm in a column having a length of 10 cm, and 106 g having a boiling point of 120°-125° C. at 0.5 mm Hg were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C[Si]([C:27]#[N:28])(C)C.[OH-].[NH4+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=2)([C:27]#[N:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(Nc2cccc(F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 1-benzyl-4-piperidinone (25.0 g, 132 mmol) in acetic acid (132 ml) at 0° C. were added 3-fluoroaniline (12.7 ml, 132 mmol) and trimethylsilyl cyanide (17.6 ml, 132 mmol) dropwise. The reaction was allowed to warm to rt and stir for 18 h. The reaction was poured onto a mixture of ice (200 g) and ammonium hydroxide (200 ml), and the product was extracted with dichloromethane (4×500 ml). The combined organic extractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown solid. The crude material was recrystallized from diethyl ether to afford 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carbonitrile as a beige solid (67%). LCMS. (M+H) 310.1. 1H NMR (400 MHz, DMSO) δ 7.33 (m, 4H), 7.25 (m, 1H), 7.19 (q, J=7.8 Hz, 1H), 6.66 (dd, J=8.2, 2.0 Hz, 1H), 6.59 (dt, J=12.2, 2.2 Hz, 1H), 6.50 (td, J=8.5, 2.2 Hz, 1H), 6.42 (s, 1H), 3.52 (s, 2H), 2.76 (d, J=11.2 Hz, 2H), 2.30 (t, J=10.9 Hz, 4H), 1.82 (t, J=10.5 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](Cl)=[N:9][CH:8]=[N:7]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+].[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=1)[CH2:36][N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[N:38]1>CC#N.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH2:2][C:3]2[CH:4]=[CH:5][N:6]3[C:11]=2[C:10]([NH:46][C:42]2[CH:41]=[C:40]4[C:45](=[CH:44][CH:43]=2)[N:37]([CH2:36][C:35]2[CH:47]=[CH:48][CH:49]=[C:33]([F:32])[CH:34]=2)[N:38]=[CH:39]4)=[N:9][CH:8]=[N:7]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: Clc1ncnn2ccc(CBr)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
A suspension of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (61 mg, 0.25 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 10 equiv) and NaHCO3 (42 mg, 2 equiv) in dry CH3CN (0.5 mL) under N2 was left stirring at RT for 3 days. 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine (54 mg, 0.9 equiv) and additional NaHCO3 (42 mg, 2 equiv) were added and the reaction was left stirring overnight. The reaction was diluted with DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded 4-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxy}-piperidine-1-carboxylic acid tert-butyl ester as a foam (47 mg, 33%). This was treated with a mixture of DCM (1.5 mL) and TFA (1 mL) for 40 min and then the solvents were removed. The residue was taken up in DCM, washed with sat. aq. NaHCO3 solution, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 5% MeOH) afforded the pure amine (11 mg, 29%) as an oil. 1H NMR (CDCl3) δ 1.1-1.3 (m, 2H), 1.7-1.9 (m, 4H), 2.5-2.6 (m, 2H), 3.0-3.1 (m, 2H), 3.44 (d, 2H, J=7 Hz), 4.85 (s, 2H), 5.59 (s, 2H), 6.55 (d, 1H, J=2 Hz), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 4H), 7.97 (s, 1H), 8.05 (s, 1H), 8.20 (d, 1H, J=2 Hz), 9.70 (s, 1H); MS: 486 (M+H)+; HPLC Ret Time: 1.35 min (YMC S7 C18, 3.0×50 mm, 2 min gradient, 5 mL/min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[S:23]1C2C(=CC=CC=2)C(NC2C(CC)=NC=C(CC)N=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCSc3ccccc32)n1
Product: CCc1nc(NC2CCSc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.28, 7.19, 7.04, 5.38, 4.50, 3.53, 2.99, 2.84, 2.64, 2.55, 2.13, 1.31, 1.24; 13C NMR (100 MHz, CDCl3) δ 152.50, 149.99, 141.71, 134.14, 134.03, 131.10, 128.59, 127.30, 125.65, 124.88, 48.74, 29.40, 27.58, 25.83, 23.05, 12.52, 11.26; HRMS (EI) calcd for C17H20BrN3S 377.0562, found 377.0565.
Reaction SMILES: C(OC1C=[CH:9][C:8]([C:11]#N)=[CH:7][CH:6]=1)C=C.[I:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(Br)CC(C)C.C(=O)([O-])[O-:28].[K+].[K+]>>[I:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:28][CH2:6][CH2:7][CH:8]([CH3:11])[CH3:9])[CH:15]=1
Reactant: C=CCOc1ccc(C#N)cc1
Reactant: Oc1ccc(I)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCBr
Product: CC(C)CCOc1cc(I)ccc1O

Procedure:
Using the method described in Example 48 for the preparation of 4-cyanophenol allyl ether, 4-iodophenol was reacted with isoamylbromide in the presence of potassium carbonate to give 4-iodo-isoamyloxyphenol as an oil, NMR(CDCl3): 0.95(6H,d), 1.66(2H,q), 1.68-1.92(1H,m), 3.93(2H,t), 6.63-6.72(2H,d), 7.49-7.59(2H,d); m/z290(M).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].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.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]2[CH:53]([NH:54][CH3:55])[CH2:52][N:51]([C:56]([CH:58]3[CH2:63][CH2:62][N:61]([C:64]([C:66]4([CH3:69])[CH2:68][CH2:67]4)=[O:65])[CH2:60][CH2:59]3)=[O:57])[CH2:50]2)[CH:45]=[CH:46][C:47]=1[Cl:48]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]2[CH2:50][N:51]([C:56]([CH:58]3[CH2:59][CH2:60][N:61]([C:64]([C:66]4([CH3:69])[CH2:67][CH2:68]4)=[O:65])[CH2:62][CH2:63]3)=[O:57])[CH2:52][CH:53]2[N:54]([CH3:55])[C:5](=[O:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])[CH:45]=[CH:46][C:47]=1[Cl:48]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCC(F)(F)F)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 4,4,4-trifluorobutyric acid (43 mg, 0.304 mmol) in NMP (1 ml) was added at ambient temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (89 mg, 0.28 mmol) and N,N-diisopropyl ethyl amine (130 μl, 0.760 mmol). After stirring for 15 min a solution {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (111 mg, 0.253 mmol) in NMP (1 mL) was added and stirred for 18 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with aqueous sodium carbonate (1 M, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=20:80:0 to 0:85:15) afforded the title compound (109 mg, 77%) as an off-white foam. MS m/e: 562.2 [M]+.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([CH2:22][CH2:23][NH:24][CH2:25]4)=[CH:20][CH:19]=3)[N:15]3[N:35]=[CH:36][CH:37]=[C:14]3[N:13]=2)=[O:10])=[CH:38][CH:39]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(NC(=O)c4ccc(C(C)(C)O)cc4)nc4ccnn34)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)CNCC4)n3nccc3n2)cc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
tert-Butyl 7-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from Step A was dissolved in CH2Cl2 (2 ml). Trifluoroacetic acid (2 ml) was then added at 0° C. The mixture was stirred for 30 minutes at that temperature before being concentrated in vacuo. Residual trifluoroacetic acid was removed azeotropically with toluene twice. The residue was then dissolved in acetonitrile before being purified by preparatory HPLC (20-30% MeCN/H2O gradient+0.01% TFA) to give the titled compound as a white powder (50 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.30 (s, 1H), 9.14 (br. s., 2H), 8.21 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.05-8.01 (m, 2H), 8.00-7.95 (m, 1H), 7.65-7.60 (m, 2H), 7.50 (d, J=8.1 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 4.47-4.40 (m, 2H), 3.47 (br. s., 2H), 3.13 (t, J=6.2 Hz, 2H), 1.46 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([SH:18])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:19])[CH2:10][CH2:11][NH:12][C:13]([S:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])C=C(S)NCCNCc1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCNC(=C[N+](=O)[O-])SCc1ccccc1)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
The compound synthesized in Example 2 (1.4 g) was dissolved in dry acetonitrile (30 ml), and potassium carbonate (1.4 g) was added. The mixture was stirred at room temperature for 30 minutes. Then, benzyl bromide (0.9 g) was added, and the mixture was heated at 50° C. for 2 hours with stirring. The reaction mixture was cooled to room temperature, and poured into water for neutralization. The aqueous layer was extracted with dichloromethane. The crude product was purified by silica gel column chromatography to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-benzylthio-2-nitrovinyl)ethylenediamine (0.3 g) having a melting point of 119° to 123° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:34]=[CH:33][CH:32]=[C:17]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:16]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (665 mg, yield 72%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3 volume ratio).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(Br)C=C.Cl>O1CCCC1.CCCCCC>[C:22]([O:21][C:19]([NH:18][CH2:17][CH:16]([CH2:3][CH:1]=[CH2:2])[C:15]([O:14][CH3:13])=[O:26])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Dissolve diisopropylamine (5.6 mL, 40 mmol) in anhydrous tetrahydrofuran, cool to -78° C. and place under nitrogen atmosphere. Treat with n-butyllithium (25 mL of a 1.6M solution in hexane, 40 mmol). Stir for 30 minutes and add, by dropwise addition, a solution of N-(t-butyloxycarbonyl)-β-alanine methyl ester (4.06 g, 20 mmol) in tetrahydrofuran (25 mL) over 20 minutes. Stir for an additional 30 minutes. Add allyl bromide (1.72 mL, 20 mmol) and allow the mixture to warm to room temperature with stirring until homogeneous. Cool to -78° C. and slowly warm to -20° C. over 30 minutes. Pour into 5% hydrochloric acid, extract into ether, wash with saturated sodium chloride, dry, and concentrate to yield 5.01 g yellow oil. Purify by silica gel chromatography (25% ethyl acetate/hexane) to yield 4.2 g (87%) of a racemic mixture of the title compound as a clear colorless oil.
Reaction SMILES: C([Li])CCC.CN(C)[CH2:8][CH2:9]NC.[Cl:13][C:14]1[CH:21]=C[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.IC>CCCCCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:8]([CH3:9])[CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CNCCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C=O
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (30.4 ml, 2.5M) was added dropwise with stirring under nitrogen to a solution of N,N,N'-trimethylethylenediamine (7.9 g) in dry THF (150 ml) at -15 to -20° C. After the addition the mixture was stirred at -23° C. for 15 minutes and then 4-chlorobenzaldehyde (10.0 g) was added dropwise at -15 to -20° C. After the addition the mixture was stirred at -23° C. for 15 minutes and then more n-butyllithium in hexane (85.4 ml, 2.5M) was added dropwise at -15° C. The mixture was stirred at -23° C. for 3 hours, cooled to -40° C. and iodomethane (60.6 g) added at -40° to -20° C. After the addition, the mixture was stirred at -40° C. for 5 minutes and then allowed to warm up to ambient temperature and then stirred at that temperature for 30 minutes. The mixture was carefully poured into ice cold 10% hydrochloric acid (2 1) and left standing for 64 hours. The mixture was extracted with diethyl ether to give an oil which was distilled twice under vacuum to give 4-chloro-2-methylbenzaldehyde, b.p. 105°-110° (15 mmHg) which was sufficiently pure for synthetic use in Example 40.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](OC)=[CH:10][C:9]=2[OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>CC(=O)CC>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:23][CH:25]2[O:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(-c2ccccc2OCC2CO2)nn1

Procedure:
i. A stirred mixture of 6-chloro-3-(2-hydroxy-4-methoxyphenyl)pyridazine (0.1 mole), potassium carbonate (0.3 mole) and epibromohydrin (0.4 mole) in butan-2-one was heated under reflux overnight. The filtered solution was evaporated to give an oil which was purified by elution with mixtures of chloroform-methanol on a silica column to give 6-chloro-3-[2-(2,3-epoxypropoxy)phenyl]pyridazine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([O:6][C:7]2[C:8]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:21][N:20]([CH2:29][OH:30])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.[C:31](=[O:34])(O)[O-].[Na+].[C:36](OCC)(=O)[CH3:37]>>[OH:30][CH2:29][N:20]1[C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=[C:7]([O:6][C@H:4]3[CH2:3][C@H:2]([NH:1][C:31](=[O:34])[CH:36]=[CH2:37])[CH2:5]3)[C:8]=2[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21]1
Reactant: O=C([O-])O
Reactant: Cn1cc(Nc2nc(O[C@H]3C[C@H](N)C3)c3c(-c4ccccn4)cn(CO)c3n2)cn1
Reactant: CCOC(C)=O
Agent: [Na+]
Product: C=CC(=O)N[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3c2c(-c2ccccn2)cn3CO)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of {4-[(trans-3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl}methanol in ethyl acetate (5 mL) was added saturated aqueous sodium bicarbonate (5 mL) and stirred at ambient temperature for 15 min and then added acroyl chloride (53.6 mg, 0.592 mmol) and stirred at ambient temperature for 2 hours. The volatiles were removed to give N-(trans-3-{[7-(hydroxymethyl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}cyclobutyl)prop-2-enamide. Ethanol (10 mL) was then added to the residue, followed by potassium carbonate until the pH of the reaction mixture was about 12. The reaction mixture was then stirred at ambient temperature for 2 hrs. The solid was then removed and the volatiles were concentrated down in vacuo and purified by preparative SFC method using a Zymor, Inc. Pyr/Diol, 150×21.2 mm, 5 μm column using the ethanol/CO2 with flow rate 50.0 mL/min using gradient 20%-40% ethanol ramp at 4%/min, hold 40% ethanol for 0.5 min which was then lyophilized to afford the title compound (18.8 mg, 7.4% yield) as a white solid. 1H NMR (700 MHz, DMSO) δ ppm 11.41-11.96 (m, 1H) 8.88-9.01 (m, 1H) 8.57-8.63 (m, 1H) 8.52-8.55 (m, 1H) 8.10-8.15 (m, 1H) 7.87-7.93 (m, 1H) 7.80-7.85 (m, 1H) 7.47-7.55 (m, 2H) 7.18-7.24 (m, 1H) 6.21-6.32 (m, 1H) 6.09-6.15 (m, 1H) 5.61-5.67 (m, 1H) 5.52-5.60 (m, 1H) 4.42-4.52 (m, 1H) 3.78-3.86 (m, 3H) 2.52-2.56 (m, 4H). m/z (ESI+) for C22H22N8O2 431.1 (M+H)+.
Reaction SMILES: [OH-:1].[K+].[NH:3]1[C:10](=[S:11])[NH:9][C:7](=[S:8])[NH:6][C:4]1=[S:5].Br[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:16])=[O:15]>C(O)C>[N:3]1[C:10]([S:11][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:16])=[O:15])=[N:9][C:7]([S:8][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:15])=[O:1])=[N:6][C:4]=1[S:5][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:16])=[O:15]
Reactant: [OH-]
Reactant: S=c1[nH]c(=S)[nH]c(=S)[nH]1
Reactant: CCCCCCCCCCC(Br)C(=O)O
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCC(Sc1nc(SC(CCCCCCCCCC)C(=O)O)nc(SC(CCCCCCCCCC)C(=O)O)n1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of KOH (12.8 g; 0.228 mole) in ethanol (350 ml) is cooled to 10° C. and treated with trithiocyanuric acid (6.8 g; 0.038 mole). After stirring for 30 minutes, the reaction mixture is treated with 2-bromododecanoic acid (31.8 g; 0.114 mole) in small portions over 10-15 minutes. The resulting thick, white suspension is stirred for a further 30 minutes at 10° C. and is then allowed to warm to ambient temperature. Upon reaching ambient temperature the reaction mixture is heated to reflux and maintained at this temperature for 6 hours.