Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]([C:15](=O)[CH3:16])[C:13]#[N:14])[CH:3]=1.Cl.Cl.[NH2:20][NH2:21].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([C:12]2[C:15]([CH3:16])=[N:20][NH:21][C:13]=2[NH2:14])[CH:3]=1
Reactant: NN
Reactant: CC(=O)C(C#N)c1cc(F)c2c(c1)OCCO2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1cc(F)c2c(c1)OCCO2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxobutanenitrile (0.37 g; 1.56 mmol) was dissolved in dry ethanol (5 mL) and hydrazine dihydrochloride (0.20 g, 1.87 mmol) then triethylamine (217 μg, 1.56 mmol) were added. The reaction mixture was refluxed for 2 h, cooled to rt and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2×25 mL), brine (25 ml) then dried over sodium sulfate. Filtration and concentration gave 4-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-1H-pyrazol-5-amine (0.36 g, 93% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 6.75 (dd, 1H), 6.65 (m, 1H), 4.30 (m, 4H), 2.14 (s, 3H). MS (EI) for C12H12FN3O2: 250 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:34][Si](C=[N+]=[N-])(C)C.CCCCCC.[Cl:47]CCl>>[ClH:47].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH3:34])[C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:22])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Reactant: ClCCl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Product: CN(c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1)S(=O)(=O)c1ccc(S(C)(=O)=O)cc1
Product: Cl

Procedure:
To a stirred solution of 4-methanesulfonyl-N-[4-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide (Example 22) (0.028 g, 0.057 mmol) in 2 ml dichloromethane (2 mL) is added 2 M (trimethylsilyl)diazomethane in hexane (0.063 ml, 0.126 mmol) and allowed to react for 5 hours at ambient temperature. The reaction is diluted with dichloromethane and washed with 0.1 N HCl. The organic layer are dried over anhydrous sodium sulfate, filtered, and concentrated to an oily solid. The oily solid is converted to the hydrochloride salt in accordance with the preparation of the title compound of Example 23 (C-Phenyl-N-[4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-methanesulfonamide; hydrochloride) to provide the title compound as a solid. MS (ES+) m/e 506.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([O:30][CH2:29][C:28]([F:27])([F:38])[F:39])[CH:32]=1)=[O:6]
Reactant: Nc1cccc(OCC(F)(F)F)c1
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(OCC(F)(F)F)c1)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Under nitrogen, to 2-chloro-6-nitrobenzoic acid (1.27 g, 6.28 mmol, 1.00 equiv) in CH2Cl2 (20 mL) at 23° C. was added oxalyl chloride (0.585 mL, 6.91 mmol, 1.10 equiv) and DMF (16 μL, 0.19 mmol, 3.0 mol %). After stirring for 1 hr at 23° C., the reaction mixture was cooled to 0° C. and triethylamine (2.63 mL, 18.8 mmol, 3.00 equiv) and 3-(2,2,2-trifluoroethoxy)aniline (1.20 g, 6.28 mmol, 1.00 equiv) were added. After stirring for 15 min at 0° C., 3N HCl aq (50 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×3.0 mL). The combined organic phases were washed with brine (3.0 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 965 mg of the title compound (41% yield).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:19][CH2:18][C:17]([F:25])([F:16])[C:21]([F:24])([F:23])[F:22])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCC(F)(F)C(F)(F)F
Product: O=S(=O)(OCCC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 56 °C
Reaction time: 2 h

Procedure:
198.49 g (703.51 mmol) of trifluoromethanesulphonic anhydride were initially charged under argon. The flask was immersed in an oil bath having a temperature of 70° C. and heated to an internal temperature of 56° C. 88.2 ml (738.68 mmol) of 3,3,4,4,4-pentafluorobutanol were added dropwise over a period of 35 min to the reaction mixture. The mixture was stirred at a bath temperature of 70-73° C. and an internal temperature of 69° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was taken up in 1500 ml of dichloromethane. The mixture was washed once with 300 ml of cold water, once with 300 ml of cold aqueous saturated sodium bicarbonate solution and once with 300 ml of cold water. The organic phase was dried with magnesium sulphate, filtered off and concentrated. This gave 192.86 g (92.6% of theory) of the target compound.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:28]([O:55][CH3:56])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:53][CH3:54])[C@@H:38]([CH3:52])[C:39]([NH:41][C@H:42]([CH3:51])[C@@H:43]([OH:50])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:40])=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.C(NCC)C>>[OH:50][C@@H:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:42]([NH:41][C:39](=[O:40])[C@H:38]([CH3:52])[C@H:37]([C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][C@@H:28]([O:55][CH3:56])[C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:21])[CH3:22])[NH2:18])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[O:53][CH3:54])[CH3:51]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
To a stirring solution of #132 (1.33 g, 1.60 mmol, 1.0 eq) in 10 mL of THF diethylamine (5 mL, 50 mM, 31.3 eq) was added. The reaction was allowed to stir at room temperature for 4 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #133 (418 mg, 43%) as a white solid. LC-MS (Protocol Q1): m/z 605.2 [M+H+] retention time=1.48 minutes.
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:36])[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:3]=2[N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:36])[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH2:21]2)[NH:8][CH:9]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.[C:37]1([C:2]2[C:3]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[C:4]3[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Product: O=C(Nc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12)c1cccnc1
Temperature: 150 °C
Yield: 31 %
Yield: 15 %

Procedure:
tert-Butyl 2-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.090 g, 0.16 mmol) and phenylboronic acid (0.039 g, 0.32 mmol) were placed in dioxane (1.5 mL) and degassed for 30 minutes. A 20% Na2CO3 (0.5 mL) solution was then added, followed by the addition of PS-Pd(PPh3)4 (0.081 g, 0.0081 mmol). The reaction was then heated in a microwave at 150° C. for 1 hour. The reaction was next diluted with DCM and filtered to remove the catalyst The reaction was then purified by prep HPLC to give a mixture of tert-butyl 2-(4-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.013 g, 15% yield) and N-(5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.020 g, 31% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH2:39]([OH:41])[CH3:40].C(N(CC)CC)C>ClCCl>[CH2:39]([O:41][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22])[CH3:40]
Reactant: CCO
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 56 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride (0.1 g) in dry dichloromethane (5 mL) was treated with absolute ethanol (0.2 g) and triethylamine (0.1 g) for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (1:4 to 2:3 by volume) to afford the title compound as a white solid (0.057 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.77 (dd, 1H), 7.48-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.61 (d, 1H), 6.40 (d, 1H), 4.37 (d, 1H), 4.17 (qd, 2H), 3.80 (t, 5H), 3.66 (t, 4H), 3.29 (d, 1H), 2.95-2.86 (m, 1H), 2.57 (d, 1H), 2.44-2.34 (m, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[C:14]2[CH2:27][C:28]([O:30]CC)=O)(=[O:6])[O:4][CH3:5].[Al]([NH2:36])(C)C.O.Cl>C1(C)C=CC=CC=1.C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[C:14]2[CH2:27][C:28]([NH2:36])=[O:30])(=[O:6])[O:4][CH3:5]
Reactant: C[Al](C)N
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OCCCP(=O)(OC)OC)cc12
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1)OC
Temperature: 50 °C
Yield: 80 %

Procedure:
[3-[[3-(2-Ethoxy-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (590 mg, 1.3 mmol) was dissolved in 40 mL of toluene and 10 mL of 0.67M (CH3)2AlNH2 in benzene/toluene were added. The mixture was heated at 50° C. for 3.25 hours and water and 1N HCl added. The mixture was extracted with a large volume of ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with a gradient, 1% MeOH/methylene chloride→4% MeOH/methylene chloride, to give 450 mg (80% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:39]1([O:38][C:36]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)amine (86) (100 mg, 0.26 mmol), triethylamine (0.091 mL, 0.656 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (10 mL) is added phenyl chloroformate (0.033 mL, 0.262 mmol), and the mixture is stirred at RT overnight. The reaction mixture is diluted with dichloromethane and washed with water, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane: EtOAc (70:30-60:40) gives 100 mg of the product 123. 1H NMR (CDCl3) δ 7.50-7.40 (m, 2H), 7.40-7.10 (m, 6H), 7.10-6.90 (m, 8H), 6.90-6.80 (m, 2H), 6.70-6.60 (m, 2H), 5.75-5.55 (m, 2H), 4.75-4.55 (m, 2H); MS: m/z 466 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C(F)(F)F)n[nH]1
Temperature: 180 °C
Yield: 20.8 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Method 23, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours.) The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (50 mg) 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 2H) 8.16 (s, 1H) 8.08 (s, 1H) 5.77 (s, 1H) 5.13 (m, 1H) 2.12 (s, 3H) 1.43 (d, 3H); m/z 383.
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH:11][C@H:12]([CH2:16][OH:17])[CH2:13][CH2:14][CH3:15])[CH2:9][CH3:10].[S:18](Cl)(Cl)=[O:19].O>ClCCl>[CH2:8]([N:11]1[CH:12]([CH2:13][CH2:14][CH3:15])[CH2:16][O:17][S@@:18]1=[O:19])[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCN[C@H](CO)CCC
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC1CO[S@](=O)N1CCC
Temperature: 25 °C
Yield: 79 %

Procedure:
N-Methylmorpholine (27.3 mL) was added to a solution of (S)—N-propylnorvalinol (11.5 g) in dichloromethane (200 mL) under stirring at room temperature. A solution of thionyl chloride (9.32 mL) in dichloromethane (64 mL) was added dropwise to the resulting light yellow solution under ice-cooling and stirring. The resulting suspension was stirred at room temperature. Water was added to the suspension under ice-cooling and stirring, and the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous 1 mol/L hydrochloric acid solution and subsequently with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was dried under reduced pressure at room temperature overnight to give (S)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide as a colorless oil (16.1 g, 79% yield, cis:trans=about 38:62 determined from the integration ratio in 1H-NMR).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([C@@:11]1([OH:27])[C@@H:15]([CH2:16][OH:17])[O:14][C@@H:13]([N:18]2[CH:25]=[CH:24][C:22]([NH2:23])=[N:21][C:19]2=[O:20])[C@@H:12]1[OH:26])#[CH:10].N1C=CN=C1>CN(C)C=O>[Si:1]([O:17][CH2:16][C@H:15]1[O:14][C@@H:13]([N:18]2[CH:25]=[CH:24][C:22]([NH2:23])=[N:21][C:19]2=[O:20])[C@H:12]([OH:26])[C@:11]1([C:9]#[CH:10])[OH:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@]1(O)[C@@H](CO)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyldimethylsilylchloride (12.5 g, 82.5 mmol) was gradually added under ice-cooling to a solution of 3′-ethynylcytidine (hereinafter referred to as ECyd) (20 g, 75 mmol) and imidazole (12.8 g, 188 mmol) in N,N-dimethylformamide (hereinafter referred to as DMF) (75 mL), and the mixture was stirred for 5 hours at room temperature. After completion of reaction, the solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate (100 mL) and saturated brine (100 mL) and dried with magnesium sulfate. Magnesium sulfate was removed through filtration. The filtrate was stirred at room temperature, and precipitated crystals were collected through filtration, to thereby yield Compound 1 (11.5 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17](OCC)=[O:18])=[N:15][N:16]=2)[N:13]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:36][CH:35]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Yield: 40.6 %

Procedure:
A solution of ethyl 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (41 mg, 0.10 mmol) and (4-(trifluoromethyl)phenyl)methanamine (29 μL, 0.2 mmol) in methanol (0.5 mL) was stirred at room temperature for 16 h. Analysis by HPLC/MS indicated the staring material had been consumed. The resulting suspension was filtered, the collected solid was washed with hexanes (5 mL×2), dried in air to afford 22 mg (41%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.93 min, (M+H)+=542.2.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(c2cccc(O)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CCCCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1

Procedure:
Beginning with 3-(1-butyl-piperidin-4-yl)-phenol and methanesulfonyl chloride. MS m/z (rel. intensity, 70 eV) 311 (M+, 3), 268 (bp), 189 (20), 131 (18), 79 (12);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][N:9]4[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=3)=[O:29])=[CH:26][N:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (122 mg, 0.5 mmol) in DCM (2 ml) was added 6-phenylnicotinic acid (D48) (119 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.6 mmol) and 4-dimethylaminopyridine (7 mg, 0.06 mmol) and the reaction stirred at ambient temperature for until complete by tlc. The mixture was then washed with 2M sodium hydroxide solution (1 ml), dried over magnesium sufate and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 20% EtOAc/60-80° C. petroleum ether gave an off-white solid which was recrystallised from EtOAc/60-80° C. petroleum ether giving the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.10 (d, 1H), 8.20 (m, 2H), 8.04 (m, 2H), 7.86 (br, 1H), 7.82 (dd, 1H), 7.72 (br, 1H), 7.50 (m, 3H), 7.19 (1H, d), 3.84 (m, 2H), 2.84 (m, 2H), 2.06 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C[O:12][CH2:11][CH2:10]1.[Li+].CC([N-]C(C)C)C.C1OC1>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][OH:12])[N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CO1
Solvent: O
Product: OCCCc1cccc(F)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
To a solution of 2-fluoro-6-methylpyridine (27 mmol) in 65 ml of freshly distilled THF was added via syringe 13.5 ml of 2M LDA, and the resulting mixture was stirred at -78° C. for 20 min. To the above cold solution was added 4 ml of 4M ethylene oxide and the mixture was allowed to warm to room temperature with stirring. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2x) and brine, and dried over sodium sulfate. The organic solution was concentrated, and the residue was purified by flash chromatography (chloroform/ethanol, 10:1) to yield 1.3 g (30.9%) of 2-fluoro-6-(3-hydroxypropyl)pyridine, as a yellow oil.