Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[C:17]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Sodium bicarbonate (12.6 g) was dissolved in distilled water (250 ml) and tyramine (20.6 g) added. The resulting suspension was heated to boiling to dissolve the tyramine, then cooled to room temperature. Benzyl chloroformate (25.6 g) was added while stirring and with occasional vigorous shaking. After stirring and shaking for an additional 1.5 hours, the precipitate was filtered off and washed with distilled water. The solid was dissolved in ether (250 ml) and washed with distilled water. The organic layer was dried over MgSO4 and evaporated in vacuo to give a residue which solidified upon cooling. Recrystallization from ether/hexane gave the desired product as colourless crystals, m.p. 96°-98° C.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][C:10]([CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)([CH3:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C)C=O>[Si:5]([N:17]1[CH:14]([C:10]([CH3:13])([CH3:9])[CH:11]=[CH2:12])[CH2:15][C:16]1=[O:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: C=CC(C)(C)C1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(C)(C)C1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyldimethylchlorosilane (7.51 g) is added in one portion to an ice-cold, stirred solution of 4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (6.54 g) and triethylamine (5.04 g) in anhydrous dimethylformamide (100 ml). The reaction mixture is stirred at 0°-5° C. for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5N hydrochloric acid (50 ml), water (3×50 ml), and brine, dried with magnesium sulfate, filtered and evaporated under vacuum to provide crude product which is purified by chromatography on silica gel (20% ether in petroleum ether) to yield 2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:21]N1C(=O)CCC1=O.O>C(O)C>[Cl:21][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:2]=3[Cl:1])[C:7]2=[N:14][C:13]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cn2cccc(OCc3c(Cl)cccc3Cl)c2n1
Solvent: O
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)cccc3Cl)cccn2c1Cl
Yield: 56.6 %

Procedure:
To a solution of 8-(2,6-dichlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (100 mg) in ethanol (2 ml) was added in one portion N-chlorosuccinimide (65.3 mg) at ambient temperature. After stirring for 1 hour at the same temperature, water was added thereto, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with 1% solution of methanol in methylene chloride. The desired residue was recrystallized with a mixture of benzene and n-hexane to give 3-chloro-8-(2,6-dichlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (63 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]([Cl:16])([Cl:15])[CH2:13]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[C:1]([O:10][CH2:13][C:12]([Cl:16])([Cl:15])[Cl:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1O
Temperature: 100 °C
Yield: 59.2 %

Procedure:
--A mixture of salicylic acid (90 g), 2,2,2-trichloroethanoI (270 g) and concentrated sulphuric acid (50 g) was stirred and heated at 100° C. for 4 hours. The mixture was diluted with chloroform (800 ml) and extracted with water (2×500 ml). After further extraction with saturated aqueous sodium bicarbonate solution (1000 ml), the organic layer was washed with water (2×500 ml) and dried (Mg SO4). The chloroform and excess trichloroethanol was removed in vacuo (65° C./20 mmHg) and the product was distilled (110°-112° C./0.5 mmHg) to give 2,2,2-trichloroethyl salicylate (104 g, 59% ) as a clear liquid which solidified on cooling.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(Br)cc3c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2oc3c(COS(C)(=O)=O)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a mixture of the product of Example 74, step E (300 mg, 0.78 mmol) in dichloromethane (4 mL) at 0° C. was added triethylamine (93 mg, 0.92 mmol) followed by methanesulfonyl chloride (100 mg, 0.88 mmol). The reaction mixture was allowed to warm to ambient temperature over 2 h, then treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 95:5 hexanes/ethyl acetate) provided tert-butyl 8-bromo-6-((methylsulfonyloxy)methyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (340 mg, 94%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.59 (s, 1H), 7.44 (s, 1H), 5.47 (s, 2H), 4.52 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.02 (s, 3H), 2.88 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].Br[CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10](OCC)=[O:11]>C(O)C>[CH2:15]([CH:9]1[S:7][CH2:6][CH2:5][NH:4][C:10]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: NCCS
Reactant: CCCCC(Br)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1SCCNC1=O

Procedure:
Potassium hydroxide (56 g) was added to a suspension of cysteamine, hydrochloride (56.6 g) in absolute ethanol (300 ml) followed by dropwise addition of ethyl 2-bromohexanoate (111.5 g). When the exothermic reaction ceased, the mixture was refluxed for 3 hours and filtered. Concentration of the filtrate in vacuo gave the title compound as a viscous oil which was used in the next step without purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[C:12](=[N:16]O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[C:18](O)(=[O:20])[CH3:19]>C(OC(=O)C)(=O)C.[Zn]>[C:18]([NH:16][CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH:8]=2)[C:13]1=[O:15])(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(=NO)CC2
Reactant: CC(=O)O
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 gm of zinc powder was added to a solution of 300 mg of the compound prepared in (2) above dissolved in a mixed solvent of 10 ml of acetic acid and 10 ml of acetic anhydride, and the mixture was stirred for 40 minutes at room temperature. Insoluble substances were removed by filtration and filtrate was concentrated. The residue was recrystallized in ethyl acetate and hexane to obtain 263 mg of the title compound.
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:24]3OCC[O:25]3)[CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH:24]=[O:25])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(C2OCCO2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenyl]-[1,3]dioxolane (3.03 g, 7.6 mmoles), and 2N HCl (4 mL, 8 mmoles) in THF (30 mL) was stirred at 40° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with waster, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum to yield the title compound (2.56 g, 7.22 mmoles).
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1.O>C(Cl)Cl>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][C:10]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1
Reactant: CC(C)(C)S(=O)Cl
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Solvent: O
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylpropane-2-sulfinic acid chloride (83 mg, 0.59 mmol) in DCM (2 mL) was added dropwise to a solution of 4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine (265 mg, 0.56 mmol), TEA (113 mg, 1.12 mmol) and DCM (3 mL) at 0° C. under Ar. The mixture was stirred at rt overnight, poured into H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization from DCM/PE gave the sub-title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][OH:14].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:14][CH2:13][CH2:12][CH:11]([CH3:10])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N+:3]=1[O-:9]
Reactant: CC(CCO)CC(C)(C)C
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(CCOc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.80 g (90%) (0.0050 moles) of 3,5,5-trimethyl-1-hexanol was reacted with 0.206 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 8.5 hours to give 2-chloro-6-(3,5,5trimethylhexyloxy)pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 4 hours to give 1-hydroxy-6-(3,5,5-trimethyl-hexyloxy) pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (45%). It was recrystallized from ethyl acetate and hexanes: mp 130.5°-131° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@@H:43]([CH3:47])[CH2:44][O:45][CH3:46])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][OH:49])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50](Cl)(=[O:52])[CH3:51]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][O:41][CH2:42][C@@H:43]([CH3:47])[CH2:44][O:45][CH3:46])=[CH:36][CH:35]=2)[C@H:13]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CC(=O)Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC(C)=O)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
Analogously to Example 2a, (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H -benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 1a) and acetyl chloride are used to afford the title compound as a colorless oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.69 (gradient I).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[C:34]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:35]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>O.ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:34]=1[CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:48][CH2:47]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Clc1cccc(N2CCOCC2)c1CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2c(Cl)cccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 168.9 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (168 mg, 1.00 mmol, 0.99 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.330 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (471 mg, 3.64 mmol, 3.59 equiv) was added dropwise. The mixture was stirred at room temperature for 2 hours. 4-[3-Chloro-2-(piperazin-1-ylmethyl)phenyl]morpholine (300 mg, 1.01 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (30 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1). The crude product (204 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 273 mg (55% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-6-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.17-7.25 (m, 1H), 7.09-7.12 (m, 2H), 5.73-5.86 (m, 1H), 3.78-3.84 (m, 6H), 3.47 (d, J=6.0 Hz, 4H), 3.00 (br, 4H), 2.60 (br, 4H). LCMS (ESI, m/z): 490 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C(C)=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.0 g), rhodium(II) acetate (dimer) (0.027 g) and toluene (30 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazopropionate (3.2 g) in toluene (30 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. A solution of ethyl 2-diazopropionate (1.6 g) in toluene (10 mL) was added, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 88%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC(C)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (example B.c15) the title compound is obtained as off white solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:27])[C:15]([CH3:26])([S:17]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:19])=[O:18])[CH3:16])[O:10][N:9]=1)([CH3:7])[CH3:6].Br[CH2:29][CH2:30][O:31][CH3:32]>C1COCC1.O>[CH3:32][O:31][CH2:30][CH2:29][O:3][CH2:4][C:5]([C:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:27])[C:15]([CH3:16])([S:17]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:19])=[O:18])[CH3:26])[O:10][N:9]=1)([CH3:7])[CH3:6]
Reactant: COCCBr
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F)on1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a solution of NaH (60% in mineral oil; 11.0 mg; 0.284 mmol) in anhydrous THF (2.0 mL) is added N-[3-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(3,3,3-trifluoro-propane-1-sulfonyl)-propionamide (50.0 mg; 0.129 mmol). The reaction is stirred at room temperature for 15 minutes and then 1-bromo-2-methoxy-ethane (0.037 mL, 0.387 mmol) is added. The reaction is stirred at 50° C. for 6 h and monitored by LC MS. Additional NaH (60% in mineral oil; 0.011 g; 0.284 mmol) and 1-bromo-2-methoxy-ethane (0.037 mL; 0.387 mmol) is added and the reaction is stirred overnight at room temperature. The crude mixture is diluted with water and extracted with ethyl acetate. The combined organics are dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound is obtained after purification by prep HPLC to afford 8 mg. Yield 14%. ESI m/z 445[M+H].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([Cl:23])[CH:3]=1.FC(F)(F)C(O)=O.C1C(=O)N([Br:38])C(=O)C1.[OH-].[Na+]>OS(O)(=O)=O>[Br:38][C:3]1[C:4]([Cl:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:6][C:2]=1[Br:1]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3Cl)c(C)nc12
Yield: 93.7 %

Procedure:
To a solution of 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (5.92 g, 14.34 mmol) and trifluoroacetic acid (40 mL) and 98% H2SO4 (10 ml) is added NBS (3.83 g, 21.15 mmol). After 10 minutes the solution is poured into ice, and made basic with 5M NaOH. The slurry is extracted with EtOAc (3×100 mL), the combined organic layers washed with water (2×400 mL), brine (400 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (6.61 g, 13.44 mmol, 94%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.92 (m, 4H), 2.47 (s, 3H), 2.52 (s, 3H), 3.25-3.34 (m, 1H), 6.72 (s, 1H). LC/MS (m/z): calcd. for C17H18Br2ClN3S (M+H)+: 489.9; found: 490.0.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:21])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](OC)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1.FC1C=CN2C(C(OCC)=O)=CN=C2C=1>>[Br:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:21])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:1])[N:9]=3)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Agent: CCOC(=O)c1cnc2cc(F)ccn12
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Yield: 62 %

Procedure:
Prepared according to Example 1, Step A, substituting 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine for 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine and methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate for ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate, to give the title compound (62%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.[CH3:23][C:24](=O)[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][C:9]1([CH3:12])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]([CH3:25])[CH3:23])[CH2:4][C@@H:5]([N:13]3[C:17]4[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=4[CH:15]=[CH:14]3)[C@@H:6]2[O:10]1
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NC[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.024 g, 3.38 mmol) was dissolved in DCE (35 ml) and propan-2-one (0.50 ml, 6.75 mmol) was added and the reaction left for 15 mins. Sodium triacetoxyborohydride (1.002 g, 4.73 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (35 ml) and DCM (35 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×35 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM and 15% 2M NH3 in MeOH:85% DCM as eluent to give the product as a white foamy solid (0.941 g, 81%): MS (ESI+) for C18H27N5O2 m/z 346.1 [M+H]+, 368.1 [m+Na]+; LCMS: Compound in solvent front; 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.04 (d, J=3.63 Hz, 1H), 6.36 (d, J=3.47 Hz, 1H), 5.08 (br. s., 2H), 4.87-5.02 (m, 2H), 4.54 (t, J=6.38 Hz, 1H), 2.80-2.90 (m, 2H), 2.70-2.80 (m, 1H), 2.46 (dt, J=12.77, 6.54 Hz, 1H), 2.30-2.37 (m, 1H), 2.17 (q, J=11.98 Hz, 1H), 1.57 (s, 3H), 1.31 (s, 3H), 1.09 (t, J=5.44 Hz, 6H).