Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@H:21]1[C@H:24]([C:25]#[C:26][Si](C)(C)C)[NH:23][C:22]1=[O:31])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+]>C(O)C.CS(C)=O.CCOCC>[C:25]([C@@H:24]1[NH:23][C:22](=[O:31])[C@H:21]1[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:26]
Reactant: C[Si](C)(C)C#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCO
Product: C#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.8 %

Procedure:
10.0 g (0.024 mol) of (3S,4S)-3-tritylamino-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone and 1.5 g (0.026 mol) of potassium fluoride are stirred at 20° C. for 1.5 hours in 100 ml of ethanol and 100 ml of dimethyl sulphoxide. The solution is diluted with ether, the ether phase is washed with water, dried and evaporated. 8.1 g (85%) of crude (3S,4S)-4-ethynyl-3-tritylamino-2-azetidinone are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
tert-Butyl 3-[2-(2-naphthyl)ethoxy]propanoate (Example 32a) (4.96 g) was dissolved in DCM (25 ml), and trifluoroacetic acid (25.5 ml) added. The mixture was stirred for 1 hour. The solvents were removed in vacuo, and the residue taken up in ether. The ether was washed with saturated bicarbonate solution (×3) and the aqueous layer was acidified with 2N HCl, then extracted with ether (×3), dried over magnesium sulfate, filtered and evaporated to give the sub-titled compound (3.66 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1.N>CO.[Ni]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1
Reactant: Cc1ncc(C2(C#N)CCCO2)cn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ncc(C2(CN)CCCO2)cn1
Temperature: 25 °C

Procedure:
2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-carbonitrile (18 mg, 0.095 mmol) was dissolved in MeOH(5 ml) and 7M NH3 in MeOH (1 ml). Argon was bubbled through the solution. Raney Nickel (6 mg, 0.1 mmol) was added and the flask was fitted with a H2-balloon and stirred at room temperature for 1½ hour. Reaction was filtred through a plug of celite and concentrated in vacuo. Used for next step without further purification. LC-MS (m/z) 194.0 (MH+), tR (minutes, Method D)=0.17.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: OC1CCc2ccc(C(F)(F)F)cc21
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc2c(c1)C(Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6-(Trifluoromethyl)indan-1-ol (1.52 g, 7.5 mmol) was dissolved in thionyl chloride (15 mL). After being stirred at room temperature for 2 hrs, the solution was concentrated in vacuo to provide the title compound (1.5 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=C(C)C.[O:39]=[O+][O-]>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=[O:39]
Reactant: C#CCN(c1ccc(C=C(C)C)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCO
Product: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: -70 °C

Procedure:
o-Fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-β,β-dimethylstyrene (0.626 g) was dissolved in a mixture of methylene chloride (2 ml) and ethanol (250 ml). The mixture was cooled to -70° C. and ozone gas was passed into the solution for 7.5 minutes. Argon gas was bubbled into the solution for 5 minutes. Dimethyl sulphide (4 ml) was added and the mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([O:8][CH2:9]OC)[CH:7]=1.Cl.[OH-].[NH4+].[C:20]([O-])([O-])=O.[K+].[K+].C(I)C>C(Cl)Cl.CO.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([O:8][CH2:9][CH3:20])[CH:7]=1
Reactant: COCOc1cc(Br)cc(N2CCCC2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(Br)cc(N2CCCC2)c1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 44.2 %

Procedure:
A flask was charged with 1-(3-bromo-5-methoxymethoxy-phenyl)-pyrrolidine (206 mg, 0.72 mmol) and a solution of 10% ethanolic hydrogen chloride (5 ml, dry) was added. The flask was capped and stirred for 45 minutes. The volatile material was stripped (rotovap) and methylene chloride (10 ml) was added. This was again stripped. The remainder was taken up in methylene chloride (10 ml). To this stirred material was added a 5% solution of ammonium hydroxide in methanol (20 drops). This material was stripped and the procedure repeated once more. The stripped remainder was taken up in dry DMF (3 ml) and K2CO3 (348 mg, 2.52 mmol) was added. Ethyl iodide (0.07 ml, 0.9 mmol) was added and the mixture was capped and stirred for 2.5 hours. Additional ethyl iodide (0.15 ml, 1.9 mmol) was added and the material was capped and heated (60° C.) over night. Ethyl iodide (0.15 ml, 1.9 mmol) was again added and the mixture capped and heated (100° C.) for 12 hours. The volatiles were removed (rotovap/pump) and the remainder was taken up in water (25 ml) and ethyl acetate (25 ml) and the material shaken in a separtatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×20 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a crude oil. The oil was purified by preparative TLC using 7% EtOAc in hexanes as eluant to provide 86 mg of 1-(3-bromo-5-ethoxy-phenyl)-pyrrolidine as a golden brown semi-viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:24])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[OH:23])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:9]([O:11][CH2:12][C@@:13]2([OH:24])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:23][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OC[C@@]1(O)CCc2c(O)cccc2C1)N(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2
Reaction time: 16 h

Procedure:
To a mixture of (2R)-2-{[N,N-di(4-fluorophenyl)-carbamoyloxy]methyl}-2,5-dihydroxy-1,2,3,4-tetrahydro-naphthalene (0.18 g) and powder K2CO3 in dry DMF (1.8 ml) was added ethyl bromoacetate (0.047 ml) at room temperature. After stirring for 16 hours, the reaction mixture was partitioned between AcOEt and water. The organic layer was washed with water, brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from n-hexane to give (2R)-2-{[N,N-di(4-flurophenyl)carbamoyloxy]methyl}-5-[(ethoxycarbonyl)methoxy]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (0.16 g) as white solid.
Reaction SMILES: C(OC([N:8]([CH2:37][C:38]1[CH:47]=[CH:46][C:41]2[O:42][CH2:43][CH2:44][O:45][C:40]=2[CH:39]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]2=[O:36])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([CH2:37][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]4=[O:36])[CH2:13][CH2:14]3)=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To 1 mL of a chloroform solution containing 0.10 g of ethyl(2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 1 mL of trifluoroacetic acid was added and stirred for 2 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1] to give 68 mg of ethyl(2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH2:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NC[C@H]1COc2cc(O)ccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc(O)ccc4O3)cc2o1
Yield: 12.8 %

Procedure:
(S)-2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (2.89 g, 16.0 mmole), 7-(3-chloropropoxy)coumarin (3.46 g, 14.5 mmole), diisopropylethylamine (12.5 ml, 72 mmole) and sodium iodide (2.20 g, 14.7 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum. The residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane, then 1% methanol/dichloromethane, and finally 3% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.45 on silica gel with 5% methanol/dichloromethane) were combined and rechromatographed on silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the pure free base (0.98 g) redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCl/isopropanol (7.0 ml) was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.71 g of white solid, monohydrochloride, m.p. 236°-239° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48](O)=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.O1CCCC1.B>C1COCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:16]([CH2:47][CH2:48][OH:49])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCO)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 3 h

Procedure:
To a stirred solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) in 4 ml of THF are added 2.2 mmol of borane tetrahydrofuran complex (1M in THF) at RT. The reaction mixture is stirred for 3 h, quenched with 60 ml of MeOH and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: N1C=CC(B(O)O)=N1.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=1)=[O:20])[CH2:13]2.BrC1C=C2C(=CC=1)CN(C(NC1C=C[C:53]([C:56](=O)[NH:57][CH2:58][CH2:59][CH3:60])=CC=1)=O)C2>>[CH:31]1([CH2:30][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:59]5[CH:58]=[N:57][CH:56]=[CH:53][CH:60]=5)[CH:11]=4)[CH2:15]3)=[O:20])=[CH:23][CH:24]=2)=[O:36])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: OB(O)c1cc[nH]n1
Product: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(-c4cccnc4)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 280, substituting pyridin-3-ylboronic acid for 1H-pyrazol-3-ylboronic acid and 5-bromo-N-(4-(2-cyclopentylacetamido)phenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.70 (bs, 1H), 8.93-8.89 (m, 1H), 8.58 (dd, J=4.7, 1.6 Hz, 1H), 8.33 (s, 1H), 8.13-8.05 (m, 1H), 7.72 (bs, 1H), 7.71-7.64 (m, 1H), 7.54-7.44 (m, 6H), 4.81 (bs, 4H), 2.31-2.18 (m, 3H), 1.82-1.68 (m, 2H), 1.68-1.43 (m, 4H), 1.26-1.11 (m, 2H); MS (ESI(+)) m/e 441 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:12]OS(C1C=CC(C)=CC=1)(=O)=O)[C:10]#[N:11].C(N(CC)CC)C.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32][SH:33]>C(O)C>[NH2:11][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[N:12][S:33][C:32]=1[C:31]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1snc(-c2ccc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
In ethanol (100 ml), (2,4-dichlorophenyl)-O-(p-toluenesulfonyl)hydroxyiminoacetonitrile (10.0 g, 27.1 mmol) prepared in the Step 27-1-2 was dissolved, and triethylamine (3.0 g) and ethyl thioglycolate (4.72 g) were added thereto. The mixture was stirred for one hour at a room temperature. The solvent was distilled off. The residue was dissolved in diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (4.81 g, 56%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=2)[CH3:11])[N:3]=1.[NH2:24][C@@H:25]([C@H:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:29])[CH2:26][OH:27].C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+]>[C:31]([O:30][C@H:28]([CH3:29])[C@H:25]([NH:24][C:2]1[CH:7]=[C:6]([F:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:13]=[N:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=2)[CH3:11])[N:3]=1)[CH2:26][OH:27])([CH3:34])([CH3:32])[CH3:33]
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)CO
Reactant: C[C@H](Nc1nc(F)cc(F)n1)c1cnn(-c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](Nc1nc(F)cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (80 mg, 0.25 mmol), (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (55 mg, 0.28 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.63 mmol, 2.5 equiv) in DMSO (1.3 mL) was heated at 85° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (0.058 g, white solid) in 50% yield. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.66 (s, 1H), 7.61 (m, 2H), 7.13 (t, J=8.6 Hz, 2H), 5.35 (s, 1H), 5.30-5.14 (m, 2H), 5.04 (m, 1H), 3.94 (m, 1H), 3.77-3.65 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.21 (s, 9H), 1.15 (d, J=6.0 Hz, 3H). MS m/z 461.3 (M+H)+; Rt-0.88 min.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5](C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1.FC1C=C([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=2)=[S:65])C=CC=1OC1C2=C(C)C(OC)=CN2N=CN=1>C1COCC1>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:63][C:64]([NH:66][C:67](=[O:76])[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=2)=[S:65])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-morpholinoethoxy)pyrrolo[2, 1-f][1,2,4]triazin-4-yloxy)benzenamine (30 mg, 0.072 mmol, Compound C of Example 36) in 1 mL of THF was added 2-(4-fluorophenyl)ethanoyl isothiocyanate (19 mg, 0.1 mmol, Compound A of Example 2). The solution was allowed to stir at room temperature for 2 h and HPLC analysis indicated the completion of the reaction. The reaction was then quenched with NH3 in propanol and the resulting solution was loaded on a preparative HPLC to be purified. Following a work-up procedure similar to that for Compound D of Example 36, the title compound (13 mg, 30%) was obtained as a HCl salt. 1H NMR (DMSO-d6) δ 12.45 (s, 1H), 11.85 (s, 1H), 11.50 (br s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.90 (d, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.20 (m, 2H), 4.50 (br s, 2H), 4.00 (m, 2H), 3.85 (s, 2H), 3.25-3.70 (m, 8H), 2.40 (s, 3H); MS(ESI+) m/z 583.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)(=O)C.CC#N>[OH:21][CH2:20][C@@H:5]1[CH2:4][C@H:3]([O:2][CH3:1])[CH2:8][CH2:7][C@@H:6]1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CC#N
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (0.53 g) was dissolved in a mixture of 70% aqueous acetic acid (10 mL) and MeCN (10 mL) and stirred at 60° C. for 2 h. Reaction mixture was cooled and evaporated. Dissolved in EtOAc and washed with saturated NaHCO3 followed by brine and then dried (MgSO4). Filtered, concentrated and chromatographed to get benzyl (1S,2R,4R)-2-(hydroxyl methyl)-4-methoxycyclohexylcarbamate (0.24 g, yield=83%) as a clear oil. MS found: (M+H)+=294.29
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]C)=[O:13])[C:6]([CH3:16])=[C:5]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[OH-].[Na+]>CC#N.C1COCC1.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=3)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH3:16])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(Cl)cc2)c2cc(NS(C)(=O)=O)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product from step (ii) (0.688 g) in MeCN (5 ml) was added triethylamine (1.39 ml) and methanesulfonyl chloride (0.54 ml) and the reaction stirred at rt for 5 h. Further triethylamine (0.83 ml) and methanesulfonyl chloride (0.54 ml) were added and the reaction stirred for 16 h. The residue was partitioned between ethylacetate/water, the organics were separated, washed with 2M hydrochloric acid, sodium hydrogencarbonate solution, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-40% ethylacetate/iso-hexane to give a mixture of mono- and di-methanesulfonamides. This was dissolved in THF (2 ml) and a solution of 1 M sodium hydroxide (4 ml) was added and the reaction heated at 55° C. for 2 h. After cooling to RT, water (10 ml) was added and the solution extracted with ethylacetate. The aqueous solution was acidified with 2M hydrochloric acid and extracted with ethylacetate. These later organics were dried and evaporated under reduced pressure. Yield 302 mg
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 4,4'-dichlorobenzophenone (2.51 g) in isopropyl alcohol (15 ml) was added sodium borohydride (0.45 g). The mixture was stirred for 4 hours at 50° C. and poured into diluted hydrochloric acid (60 ml). The organic layer was extracted with ethyl acetate (20 ml) and washed with water (30 ml×2). The solution was dried over magnesium sulfate. The solvent was removed in vacuo to give colorless oil of bis(4-chlorophenyl)methanol (2.50 g)