Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1O[CH2:32][CH2:31]OCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[Cl:40][C:41]1[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=1>ClCCl.[Cu].ClC1C=CC=CC=1Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([N:13]([C:32]2[CH:31]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=2)[C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)=[CH:43][CH:42]=1
Reactant: Clc1ccc(I)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: CCCCCCCCc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-Octylaniline (5.00 g, 244.4 mmol), 18-crown-6 (1.29 g, 4.9 mmol), K2CO3 (27.64 g, 194.8 mmol), 1-chloro-4-iodobenzene (14.51 g, 60.9 mmol, copper (6.19 g, 97.4 mmol), and 1,2-dichlorobenzene (100 mL) were added in a 250 mL flask with a condenser connected to a Dean Stark apparatus. The mixture was heated to reflux for 24 hours under argon. The reaction mixture was then cooled to room temperature, diluted with dichloromethane, and filtered. After removal of solvent by distillation, the product was purified using silica gel column chromatography using hexane as eluant. The yield was 4.18 g (40.3%).
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)=[O:24])[CH:20]=[CH:19][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([Si:5]([CH3:10])([CH3:11])[O:6][CH2:7][CH2:8][NH:16][C:17]1[CH:22]=[C:21]([CH:23]([OH:24])[C:25]2[C:30]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=3)(=[O:34])=[O:33])=[CH:29][C:28]([Cl:46])=[CH:27][N:26]=2)[CH:20]=[CH:19][N:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(N)c2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (177.7 mg, 1.02 mmol), acetic acid (0.051 mL, 0.85 mmol) and N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (400 mg, 0.85 mmol) in DCM (3 mL) was stirred at RT for 1 hour. To the mixture was added sodium triacetoxyborohydride (360.8 mg, 1.7 mmol), stirred overnight. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by flash column to afford N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH3:20][C:21]([CH3:32])([CH3:31])[CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:24]([CH2:23][CH2:22][C:21]([CH3:32])([CH3:31])[CH3:20])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)CCNc1ccncc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: CC(C)(C)CCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(3,3-dimethylbutylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[C:11]1([CH3:40])[CH3:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(N(CC)C(C)C)(C)C>C1CCCCC1.C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([O:22][Si:23]([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[C:11]1([CH3:39])[CH3:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCCCC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.17 h

Procedure:
xi)—A mixture of (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregn-5-en-3-ol benzoate (44.6), dry toluene (394 ml), dry cyclohexane (394 ml) and N-bromosuccinimide (17.8 g) was heated at reflux temperature for 10 min. The reaction mixture was cooled, another portion of N-bromosuccinimide (17.8 g) was added, and reflux was continued for another 10 min. The reaction mixture was cooled, a saturated aqueous solution of sodium thiosulfate (802 ml) was added and the resulting mixture was stirred for 30 min. The organic phase and the aqueous phase were separated and the latter extracted two times with toluene. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A solution of the crude product thus obtained in dry toluene (1381 ml) and N,N-diisopropylethylamine (138 ml) was heated under reflux for 1.5 h. Then it was cooled and washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride and with brine, the aqueous phase each time being extracted with ethyl acetate. The combined toluene and ethyl acetate solutions were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregna-5,7-dien-3-ol benzoate (compound 12a; 40.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[CH:16]=[C:6]2[O:5][CH2:4][C:3]1=[O:17].[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:27]([CH3:28])[C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH3:34])=[N:25][N:24]=1>>[ClH:18].[CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][N:13]([CH2:19][CH2:20][CH2:21][S:22][C:23]4[N:27]([CH3:28])[C:26]([C:29]5[O:33][CH:32]=[N:31][C:30]=5[CH3:34])=[N:25][N:24]=4)[CH2:12][CH2:11][C:10]=3[CH:16]=[C:6]2[O:5][CH2:4][C:3]1=[O:17]
Reactant: Cc1ncoc1-c1nnc(SCCCCl)n1C
Reactant: CN1C(=O)COc2cc3c(cc21)CCNCC3
Product: Cc1ncoc1-c1nnc(SCCCN2CCc3cc4c(cc3CC2)N(C)C(=O)CO4)n1C
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 4-methyl-4,6,7,8,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepin-3(2H)-one (37 mg) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole and was obtained as a faint yellow slightly sticky solid (45 mg).
Reaction SMILES: [F:1][C:2]1C=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[N+:12]([O-])[C:11]([CH3:15])=[C:10]3[O:16][C:17]([CH3:21])([CH3:20])[O:18][CH2:19][C:9]=23)=[O:7])=[CH:4][CH:3]=1.CC[O:26]C(C)=O.C1(C)C=CC=CC=1.Cl[CH2:38][Cl:39]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Cl:39][C:38]1[CH:22]=[C:5]([C:6]([C:8]2[CH:13]=[N:12][C:11]([CH2:15][OH:26])=[C:10]3[O:16][C:17]([CH3:21])([CH3:20])[O:18][CH2:19][C:9]=23)=[O:7])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1c2c(c(C(=O)c3ccc(F)cc3)c[n+]1[O-])COC(C)(C)O2
Reactant: CCOC(C)=O
Reactant: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)OCc2c(C(=O)c3ccc(F)c(Cl)c3)cnc(CO)c2O1
Reaction time: 14 h

Procedure:
5.5 g of 5-(4-fluorobenzoyl)-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine 7-oxide was dissolved in 20 mL dichloromethane (DCM) in 5 mL of Trifluoroacetic anhydride (TFAA) followed by vigorous boiling. When the boiling subsided an additional 30 mL of TFAA was added and the solution was stirred overnight (14 h). TLC revealed completion of the reaction (Rf EtOAc; (s.m. 0.2), product 0.9). The DCM was removed by evaporation and the solvent switched to MeOH (100 mL). This solution was stirred for 30 min after which evaporation affording thick oil. Toluene was added and removed under high vacuum yielding a foam containing the desired product (1d).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14](I)[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1oc(-c2cc(NC(C)=O)ncc2C)nc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-iodo-1,3-oxazole-5-carboxylate (0.14 g, 0.33 mmol), (2-chlorophenyl)boronic acid (0.076 g, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.032 mmol), and cesium carbonate (0.53 g, 1.62 mmol) in 1,4-dioxane (4.5 mL) and water (0.2 mL) was subjected to microwave irradiation at 150° C. for 20 min. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added MeOH (10 mL) and aqueous NaOH (0.5 M, 1.5 mL). The mixture was allowed to stir at rt for 8 h and then concentrated to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-1,3-oxazole-5-carboxylic acid which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[N:29][CH:28]=[CH:27]3)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[N:29][CH:28]=[CH:27]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2ccc3cnccc3c2)OC1(C)C
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc4cnccc4c3)n2n1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (100 mg, 0.37 mmol), 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoquinoline (from part A, ˜1 mmol), K2CO3 (153 mg, 1.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.019 mmol) in MeCN/water (4 ml/1 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (80.8 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (t, J=7.33 Hz, 3H) 1.53 (dq, J=14.97, 7.39 Hz, 2H) 1.74-1.81 (m, 2H) 3.48-3.54 (m, 2H) 4.58 (t, J=5.05 Hz, 1H) 6.54 (d, J=9.60 Hz, 1H) 7.68 (d, J=5.56 Hz, 1H) 7.75 (d, J=9.60 Hz, 1H) 8.01-8.05 (m, 2H) 8.25 (dd, J=8.72, 1.64 Hz, 1H) 8.55 (d, J=5.81 Hz, 1H) 8.86 (s, 1H) 9.25 (s, 1H). LRMS (ESI) m/z 318.2 [(M+H)]+, calc'd for C19H19N5: 317.40.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21])(=[O:10])=[O:11]
Reactant: O=C(Cl)OCCBr
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(N(C(=O)OCCBr)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 18 h

Procedure:
1,2-Bis(methylsulfonyl)-2-(2-bromoethoxycarbonyl)-1-methylhydrazine (compound 8) was synthesized as follows: Triethylamine (1.45 g, 0.014 mol) was added in portions to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (2.02 g, 0.01 mol) and 2-bromoethyl chloroformate (3.49 g, 0.019 mol) in acetone (100 ml) over a period of 15 min. The reaction mixture was stirred for an additional 18 hr, filtered, and the filtrate evaporated to dryness in vacuo. The residue was taken up in chloroform (100 ml) and washed with water (3×20 ml). The chloroform layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to dryness. The residue was triturated with petroleum ether until a solid separated. The solid was filtered and recrystallized from ethanol (1.52 g, 43.0%). Mp was approximately 81-82° C. 1H NMR (CDCl3): δ 4.7 and 3.6 (4H, 2t, CH2CH2Br), 3.5, 3.3 and 3.1 (9H, 3s, 2CH3SO2 and NCH3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:33])(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17][Cl:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)c1ccc(-c2nc(CCCOCc3ccccc3)c(CCl)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a stirred solution of 1.5 g of {4-[3-(benzyloxy)propyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol in 15 mL of dichloromethane were added 0.484 g of methanesulfonylchloride and 1.03 mL of triethylamine. The solution was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane and poured into water. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.65 g of crude product as a yellow oil. Purification by column chromatography on silica gel (heptane 90/ethyl acetate 10) gave 0.840 g of 4-(3-benzyloxy-propyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:31][N:32]1[CH2:39][CH:38]2[CH:34]([CH2:35][CH2:36][CH2:37]2)[CH2:33]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][N:32]3[CH2:39][CH:38]4[CH2:37][CH2:36][CH2:35][CH:34]4[CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CC4CCCC4C3)n2)cc1
Yield: 67 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (34 mg, 67% yield.) MS/ES+: m/z=440.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.N.[Li].[Cl-:15].[NH4+]>O.C(O)(C)(C)C.O1CCCC1>[ClH:15].[ClH:15].[NH2:12][CH:7]([C:4]1[CH2:5][CH:6]=[CH:1][CH2:2][CH:3]=1)[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [Cl-]
Reactant: NC(CC(=O)O)c1ccccc1
Agent: N
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: NC(CC(=O)O)C1=CCC=CC1

Procedure:
To a stirred solution of DL-β-amino-β-phenyl propionic acid (16.3 g) in liquid ammonia (800 ml.), tetrahydrofuran (200 ml.) and tertiary butanol (200 ml.) contained in a vacuum jacketed vessel, was added strips of lithium (8.0 g) over a period of 4 hours when a permanent blue colour was obtained. Ammonium chloride (62 g) was cautiously added and the ammonia allowed to slowly evaporate overnight. The white residue was dissolved in water (200 ml.), the volume reduced to about 50 ml. and the pH adjusted to 5.5. The white solid was collected and recrystallised from 5N. hydrochloric acid to give β-amino-β-cyclohex-1, 4-dienyl propionic acid hydrochloride [(15.0 g m.p. 210°-212°: (found C, 52.8; H, 7.0; N, 6.8; C9H14ClNO2 requires C, 53.1; H, 6.9; N, 6.8%) n.m.r. δp.p.m. [(CD3)SO] 9.0 (3H, m); 5.85 (H, s); 5.7 (2H, s)- 3.85 (H, t); 2.7 (6H, m) i.r. γmax (mull) 2600 and 1950 (NH+), 1730 (CO), 1600 cm-1 (C = C)].
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][Si](C)(C)CCOCN1C2N=CN=C(CN)C=2C=C1.Cl>COC(OC)N(C)C.C(OCC)(=O)C>[CH:1]1([C:7]2[N:8]=[CH:26][N:14]3[C:9]=2[C:10]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:12]=[CH:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(CN)ncnc21
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(N)C3CCCCC3)ncnc21
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCCCC3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 302.6 %

Procedure:
Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanamine (10 mg. 0.028 mmol) in N,N-dimethylformamide dimethyl acetal (0.7 mL) was stirred at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 1,3-dimethylimidazolidin-2-one (1.0 mL) and stirred at 230° C. for 1.5 hours under microwave irradiation. Separately, cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylmethanamine (89 mg, 0.25 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) was stirred at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 1,3-dimethylimidazolidin-2-one (4.5 mL) and stirred at 230° C. for 1.5 hours under microwave irradiation. The reaction mixture and the previously obtained reaction mixture were combined, diluted with ethyl acetate, acidified with 1 M hydrochloric acid and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (hexane/ethyl acetate=2/1→1/1→1/2 (v/v)) to give the title compound as a pale yellow oil (31.4 mg, yield 30%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[S:17][C:16]=2[CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:19]=[C:18]([CH:20]=[O:21])[S:17][C:16]=2[CH:22]=1
Reactant: OCc1cc2ccc(Br)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
To a −78° C. solution of oxalyl chloride (1.30 mL, 14.9 mol) in CH2Cl2 (20 mL) is added a solution of dimethyl sulfoxide (2.13 mL, 29.9 mmol) in CH2Cl2 (10 mL). The mixture is stirred for 5 minutes and a solution of (6-bromo-benzo[b]thiophen-2-yl)-methanol (2.91 g; 12.0 mmoles) in CH2Cl2 (30 mL) is added. The mixture is stirred at −78° C. for 30 minutes and triethylamine (8.34 mL, 60.0 mmol) is added. The mixture is stirred for 1 hour while warming to room temperature. The reaction mixture is quenched with water (50 mL). The organic layer is separated and concentrated under reduced pressure to a residue. The residue is purified via silica gel chromatography eluting with 20% EtOAc/Hexanes to provide the title compound (2.58 g, 89%). 1H NMR (400 MHz, CDCl3): δ 10.4 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17](OCCCC)=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[NH3:26]>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:26])=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Reactant: N
Solvent: CO
Product: CCn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 3, 500 mg, 1.37 mmol) is treated with 7N ammonia in MeOH (14 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and stirred at ambient temperature for 30 mins. The resulting slurry is filtered to give the title compound, mp 211-212.5° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−25 (c 0.92, DMSO).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=[O:20])[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1.[CH3:29]I.O>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][C:25]([F:28])([F:26])[F:27])[CH:19]=[O:20])[C:8]2[O:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:15]=1
Reactant: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CO)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(-c2cc(C=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a cold solution (0° C.) of sodium hydride in tetrahydrofuran (4 mL), under an atmosphere of argon, was added 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (example 10c) (246 mg, 0.67 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at 0° C. for 15 minutes, then the argon flow was stopped and methyl iodide was added. After 3 hours at room temperature, the mixture was diluted with ethyl acetate. Water was slowly added and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to afford 99 mg of 3-(5-Methoxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde. 39% yield. 1H-NMR (300 MHz, CDCl3): 1.39 (s, 6H), 2.11 (s, 3H), 4.27 (s, 2H), 5.09 (s, 2H), 7.17 (s, 2H), 7.49 (d, J=8.5 Hz, 1H), 7.93 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 10.03 (s, 1H).