Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and 2-pyridinemethanamine (CAN 3731-51-9) as starting materials; LC-MS (UV peak area/ESI) 99.0%, 394.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[S:4][N:3]=1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2.CC(O)CC.N>CO>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Agent: N
Solvent: CCC(C)O
Solvent: CO
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C)ns5)nn34)ccnc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (548 mg, 2225 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (576 mg, 2959 μmol) were charged in a microwave vial. 2-butanol (7 mL) was added and the reaction mixture was stirred at 120° C. under micro-waves irradiation for 8 h. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (720 mg, 80% yield). MS m/z=405.1 [M+H]+. Calc'd for C19H16N8OS: 404.46
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.CN(CCN(C)C)C.CI>C1COCC1>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]([CH3:2])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: CN(C)CCN(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)Nc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
BuLi (2.2 M in cyclohexane, 22 mL, 48 mmol) was added dropwise at −78° C. to a solution of 6-chloro-1,3-dihydro-indol-2-one (4 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) under N2. The solution was stirred for 30 minutes at the same temperature and then MeI (2.2 mL, 36 mmol) was added. The reaction mixture was warmed to −20° C. and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Chromatography gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:28][NH2:29].C(O)(=O)C>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[NH:29][N:28]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)[nH]n2)cc1
Yield: 78 %

Procedure:
190 mg (0.54 mmol) methyl 4-[3-(4-butoxyphenyl)-3-oxopropanoyl]benzoate was dissolved in 10 mL ethanol and 0.5 mL hydrazine hydrate and 1 mL acetic acid were added. The mixture was refluxed for 1 h. Upon cooling, the product crystallized. To complete crystallisation, 5 mL water was added and the product was filtered off, washed with water and dried. A white crystalline material (150 mg, 0.42 mmol, 78%) was isolated and directly used for the next step.
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[N:5][C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].[BH4-].[Na+].Cl>C(O)C>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C@@H:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH3:7]
Reactant: COc1cccc(C=N[C@H](C)c2ccc([N+](=O)[O-])cc2)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN[C@H](C)c2ccc([N+](=O)[O-])cc2)c1O
Reaction time: 2 h
Yield: 90.6 %

Procedure:
8.5 g (0.0283 mole) of (R)-(-)-N-(2-hydroxy-3-methoxybenzylidene)-1-(p-nitrophenyl)ethylamine were dissolved in 150 ml of ethyl alcohol. Then, 0.54 g (0.0143 mole) of sodium borohydride was added at room temperature to the reaction mixture, which was thereafter stirred at a temperature of from 30° to 35° C. for 2 hours, and then stirred at a temperature of from 55° to 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was admixed with 30 ml of a 10% hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was dissolved in 150 ml of water, washed with 100 ml of toluene, and separated into individual layers. The aqueous layer was neutralized or weakly alkalized with a 20% aqueous sodium hydroxide solution, and extracted twice with 100 ml of toluene. The toluene layer was washed with water, and concentrated under reduced pressure to give 7.75 g of (R)-(+)-N-(2-hydroxy- 3-methoxybenzyl)-1-(p-nitrophenyl)ethylamine as crystalline substance. Yield: 90.6%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([OH:21])(=O)=[O:19])[CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([Cl:23])(=[O:21])=[O:19])[CH2:14][CH2:13]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)O)CC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonic acid (6.8 g, 22 mmol) and PCl5 (5 g, 24 mmol) was stirred at room temperature for 30 min. And then the mixture was heated at 100° C. and stirred for 2 h. After cooling to room temperature, the mixture was washed with EtOAc (150 mL×3). The combined extracts were concentrated in vacuo to give crude 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonyl chloride (5 g, 68%) as a whit solid, which was used in the next step directly.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12](OCC)=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.O.[Cl-].[Ca+2].[Cl-]>C(OCC)C>[OH:13][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: O=C=O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: OCc1nc(-c2ccccc2)cs1
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
A solution of ethyl 4-phenylthiazole-2-carboxylate (Example 4B, 1.300 g, 5.57 mmol) in diethyl ether (60 mL) in a 500 mL flask under a nitrogen atmosphere was cooled to −40° C. (dry ice-water-calcium chloride bath) and treated with solid LiAH4 (0.40 g, 10.54 mmol) added all at once. The mixture was stirred at −40° C. over 2.5 h. The reaction was quenched by dropwise addition of ethyl acetate (1 mL), water (0.4 mL) followed by 15% aqueous sodium hydroxide (0.4 mL) and water (1.2 mL). The bath was then removed and the mixture was stirred at room temperature for 50 min. The solid formed was filtered and washed with ether (50 mL). The combined filtrate and washing was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Evaporation gave a yellow oil which was purified by silica gel chromatography (2.5×8 cm, elution toluene-ethyl acetate 9:1, 8:2 to 7:3). The resulting light yellow oil (0.931 g) was then distilled in vacuo (bp: 105-110° C./0.1 torr, bulb to bulb, air bath temperature) to provide the title material (0.918 g, 86%) of a colorless syrup. LC (Method C): 1.672 min. HRMS (ESI) calcd for C10H10NOS [M+H]+ m/z 192.0478, found 192.0508. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.90 (br t, 1H), 5.02 (d, J=4.30 Hz, 2H), 7.31-7.38 (m, 1H), 7.39-7.45 (m, 2H), 7.46 (d, J=0.8 Hz, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].CO>O1CCCC1>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)O)c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CO)c1C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a stirred mixture of LiBH4 (2.62 g; 120 mmol) in tetrahydrofuran (60 mL) was slowly added, via syringe, chlorotrimethylsilane (30.1 mL; 241 mmol). After stirring for 10 minutes, 3-methoxy-2-methylbenzoic acid (10.0 g, 60 mmol) was added in small portions. The mixture was stirred at ambient temperature for 18 hours. The mixture was cooled in an ice bath and methanol was slowly added until bubbling ceased and the solution turned clear. The reaction solution was evaporated to dryness. The residue was dispersed in dichloromethane and water. The phases were separated. The aqueous phase was basified with NaOH solution to pH 9-10 extracted with dichloromethane. The extracts were combined, dried over MgSO4, and evaporated to give (3-methoxy-2-methylphenyl)methanol 25, 9.10 g, 99% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].Cl.ClCCl>N1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=1)(=[O:29])=[O:28]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a stirred solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture stirred at RT for 2 h. 2 N hydrogen chloride (aq) (20 ml) and dichloromethane (20 ml) were added and the layers separated. The aqueous layer was washed with additional dichloromethane (2×15 ml) and the organic layers combined, dried (hydrophobic frit) and evaporated in vacuo to give a brown oil. There was still some pyridine in the reaction mixture so 2M hydrogen chloride (aq) and dichloromethane (15 ml) were added to extract one more time. The solvent was removed in vacuo to give the title compound as an orange solid (4.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[Br:16]Br>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[C:9]=1[Br:16]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Br
Reaction time: 5 h
Yield: 95 %

Procedure:
3,5-Dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) was taken in 2 mL of dichloromethane, and a solution of bromine (1 mmol) in 0.5 mL of dichloromethane was added from a pressure-equalizing dropping funnel at room temperature over a period of 1.5 h. A NaOH trap system was provided on top of the addition funnel. The mixture was then stirred for 5 h and the solvent was evaporated off to give 2-Bromo-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (95%).
Reaction SMILES: [CH3:1][C:2](O)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si]([Br:24])(C)C>ClCCl.CCOCC>[C:13]1([C:2]([Br:24])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)Br
Reactant: CCCCCCCCCCC(C)(O)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(Br)c1ccccc1
Reaction time: 1 h

Procedure:
10.50 g (0.04 mol) of 1-methyl-1-phenylundecyl alcohol was dissolved in 50 ml of dichloromethane, cooled in ice bath, 10.6 ml (12.29 g, 0.08 mol) of trimethylsilyl bromide was added and the mixture stirred for 1 h under protection from moisture. The solution was diluted with 100 ml ether and washed four times with 50 ml water, brine, dried and evaporated to give crude 2-phenyl-2-bromododecane. 35 ml of 2.3 M hydrogen peroxide in THF (0.08 mol) was added to the 2-phenyl-2-dodecyl bromide and the mixture was cooled on ice bath. 8.84 g (0.04 mol) of silver trifluoroacetate was added. 70 ml of conc. NaHCO3 was added and the mixture filtered. The reaction flask and the filter cake was rinsed with diethyl ether. The aqueous phase was separated and the organic phase washed with conc. NaHCO3, 50 ml water, brine, dried and evaporated to give an oil. The oil was purified by flash chromatography using 2:8 ether:pentane as eluent. The yield of 1-methyl-1-phenylundecyl hydroperoxide was 30%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:8]3([OH:29])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[C:13](\[CH3:19])/[C:14](OCC)=[O:15])[CH2:3]1>O1CCCC1.[AlH](CC(C)C)CC(C)C.CCCCCC>[OH:15][CH2:14]/[C:13](/[CH3:19])=[CH:12]/[C@@H:11]1[C@:20]2([CH3:28])[C@@:8]([OH:29])([C@H:7]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CCOC(=O)/C(C)=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 9.60 g of ethyl (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxylate (Boutagy J. and Thomas R., Aust. J. Pharm, Chem., 1972, NS1, 67) in 370 ml of dry tetrahydrofuran, 104 ml of 1M i-Bu2AlH in hexane were added dropwise under nitrogen at -78° C. After 2 hrs the reaction was quenched with a solution of 46.0 g of sodium sulfate in 350 ml of water and stirred at room temperature for 2 hours. The mixture was then filtered through Celite and washed with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness to give 8.30 g of (E)-21-hydroxymethyl-21-methyl-5β-pregn-20-ene-3β,14β-diol as an off-white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(C(Cl)=O)=O.[NH2:22][C:23]1[S:24][C:25]([C@H:28]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:22][C:23]4[S:24][C:25]([C@H:28]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[Cl:43])[NH:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:26][N:27]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1cnc(N)s1)c1ccc(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (618 mg, 3.0 mmol) in anhydrous CH2Cl2 (6 mL) was slowly added (COCl)2 (0.3 mL, 3.4 mmol) at −10° C. followed by DMF (3 drops). The reaction mixture was stirred at −10° C. for 0.5 h. The excess (COCl)2 was removed under vacuum. The acid chloride (10.5 mmol) was then dissolved in anhydrous CH2Cl2 (3 mL) and was slowly added to a solution of (R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (648 mg, 1.8 mmol) and Et3N (1.8 mL, 6 mmol) in anhydrous CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with CH2Cl2 and washed with 1N HCl, NaHCO3 and brine. The organic layer was separated from the aqueous layer and dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40-60% EtOAc/Hexane) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)cyclopropanecarboxamide as a colorless solid (680 mg, 69%). 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.60 (dd, J=8.7, 5.9 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.3, 2.6 Hz, 1H), 7.05 (td, J=8.2, 2.6 Hz, 1H), 6.90 (td, J=8.3, 1.7 Hz, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.18 (d, J=4.3 Hz, 1H), 6.04 (s, 2H), 3.90 (d, J=4.3 Hz, 1H), 1.73 (td, J=5.4, 2.0 Hz, 2H), 1.28 (t, J=7.1 Hz, 2H), 1.29 (s, 9H). HPLC ret. time 3.65 min, 10-99% CH3CN, 5 min run; ESI-MS 550.5 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])N=[C:4]([N:9]2[C@@H:16]3[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[C:19]=1[C:20](O)=[O:21].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[C:19]=1[C:20]([N:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([N:9]([C:4]3[CH:8]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:10]2)[CH2:15]1)=[O:21]
Reactant: Cc1cc(C)nc(N2CC3CCNC[C@@H]32)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cccc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting Intermediate 40 for (1R,RS)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophene-2-yl-benzoic acid. MS (ESI) mass calcd. for O21H21FN6O, 392.4; m/z found, 393.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[C:5]2[CH2:11][N:10]([C:12]3[N:16]([CH2:17][CH3:18])[N:15]=[C:14]([CH:19]4[CH2:21][CH2:20]4)[CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:48])[C:37]=2B2OC(C)(C)C(C)(C)O2)[N:32]([S:49]([C:52]2[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=2)(=[O:51])=[O:50])[N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH:19]1([C:14]2[CH:13]=[C:12]([N:10]3[CH2:9][CH2:8][C:6]4[N:7]=[C:2]([C:37]5[C:36]([CH3:48])=[CH:35][CH:34]=[C:33]6[C:38]=5[C:30]([CH3:29])=[N:31][N:32]6[S:49]([C:52]5[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=5)(=[O:50])=[O:51])[N:3]=[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][C@H:23]5[CH3:28])[C:5]=4[CH2:11]3)[N:16]([CH2:17][CH3:18])[N:15]=2)[CH2:21][CH2:20]1
Reactant: CCn1nc(C2CC2)cc1N1CCc2nc(Cl)nc(N3CCOC[C@H]3C)c2C1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3c(B4OC(C)(C)C(C)(C)O4)c(C)ccc32)cc1
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: [Na+]
Solvent: COCCOC
Product: CCn1nc(C2CC2)cc1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc(N3CCOC[C@H]3C)c2C1
Temperature: 130 °C

Procedure:
To a solution of (R)-4-(2-chloro-6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.116 g, 0.288 mmol) in DME (1.4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole (0.129 g, 0.302 mmol), Pd(Ph3P)4 (0.033 g, 0.029 mmol) and aqueous Na2CO3 (0.43 mL, 2 M). The mixture was sparged with argon and heated in a microwave reactor at 130° C. for 1 h 20 min. The mixture was filtered and concentrated under reduced pressure. Purification by FCC (40-100% EtOAc/heptane) provided the title compound (R)-4-(6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine. MS (ESI+) m/z 667.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]([C:14]1[N:15]=[CH:16][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=1)([CH3:13])[CH3:12])(C(C)(C)C)(C)C.[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br.C(NCC)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CC#N.CO>[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][N:15]1[C:14]([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][OH:8])=[CH:18][N:17]=[CH:16]1
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCNCC
Product: CC(C)(CCO)c1cncn1Cc1ccccc1Br
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(tert-butyldimethylsilanyloxy)-1,1-dimethylpropyl]-1-trityl-1H-imidazole (650 mg, 1.27 mmol) in CH3CN (10 mL) at ambient temperature is added a solution of 2-bromobenzyl bromide (420 mg, 1.68 mmol) in CH3CN (10 mL). The resulting solution is stirred at 80° C. for 6 h. The mixture is cooled to ambient temperature and diethylamine (2 mL) is added, followed by MeOH (10 mL) and the mixture is heated at 75° C. for 1 hr and stirred at ambient temperature overnight. To the reaction mixture is added HCl/dioxane (4 M, 5 mL, 20 mmol) and stirred at ambient temperature for 1 h. The mixture is neutralized with saturated aqueous NaHCO3 and concentrated. The residue is partitioned between CH2Cl2 and brine. The organic layer is washed with brine, dried over Na2SO4 and concentrated to give an oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 323 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.CN(C=O)C.[CH3:21][S-:22].[Na+].O>[Cl-].[Na+].O>[CH3:21][S:22][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: C[S-]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Yield: 95.3 %

Procedure:
To a solution of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (2.02 g, 8.40 mmol) and DMF (40 mL) was added sodium thiomethoxide (0.618 g, 8.82 mmol). The mixture was heated to 90° C. for 50 min, then poured into brine. Water was added to bring the total volume to 300 mL and the orange precipitate was collected to yield the titled compound (2.02 g, 95%). 1H NMR (400 MHz, CDCl3): 8.42 (s, 1H), 6.51 (s, 1H), 6.39 (br s, 2H), 2.53 (s, 3H).