Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[CH:29](N(CC)C(C)C)(C)[CH3:30].ICC>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: C1COCCO1
Product: CCN1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.1 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide are dissolved in 1 ml of 1,4-dioxane, and 25 μl (0.144 mmol) of N,N-diisopropylethylamine and 10 μl (0.12 mmol) of iodoethane are added. The mixture is stirred at room temperature overnight and, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: COc1cccc(F)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(F)c1C=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 2-fluoro-6-methoxylbenzaldehyde (Compound A, 2.43 g, 15.8 mmol) and hydroxylamine hydrochloride (“NH2OH.HCl”, 1.2 g, 17.3 mmol) in ethanol (60 mL) and H2O (120 mL) was added-aq. NaOH (50% w/w 3.2 mL). The reaction mixture was stirred at room temperature for 1 hour. At the conclusion of this period, the reaction was neutralized with concentrated HCl to pH 7 and then extracted with methylene chloride (“CH2Cl2”, 3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide 2-fluoro-6-methoxybenzaldehyde oxime, Compound B, as a white solid (2.45 g, 92%). m/z (ES+) 169 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:63][C:64]([C@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)=[O:65]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@@H:66]1[C:64]([NH2:63])=[O:65])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: NC(=O)[C@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3C(N)=O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-(aminocarbonyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.I[CH3:16].O>CN(C=O)C>[CH3:16][S:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: N#Cc1ccc2nc(S)sc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Sodium hydride (60% in mineral oil, 1.92 g, 48 mmol) was suspended in DMF (60 mL) at 0° C. and 2-mercaptobenzo[d]thiazole-6-carbonitrile (5.76 g, 30 mmol) from Step 2 of this Example was added slowly. After gas evolution ceased, iodomethane (8.4 mL, 135 mmol) was added and the reaction mixture was stirred at rt overnight. To the reaction mixture was added 300 mL of water and the precipitate was collected by filtration to give 2-(methylthio)benzo[d]thiazole-6-carbonitrile as a light yellow solid (5.47 g, 89%). 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.67 (dd, J=1.5, 8.5 Hz, 1H), 2.83 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:42]([NH2:44])=[O:43])[CH2:40][CH2:41]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (6 mmol) and THF (20 mL). Cool using an ice bath. Add a 1M THF solution of tetrabutylammonium fluoride (7 mL) in dropwise fashion. After 30 minutes, concentrate in vacuo to obtain a residue. Add dichloromethane (50 mL) to the residue. Extract with water (3×15 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](O)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([Cl:22])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2cccc(OCc3ccccc3)c2n1
Product: Clc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
8-(benzyloxy)quinolin-2-ol (6.6 g, 26.3 mmol) was dissolved in POCl3 (50 mL). The mixture was stirred at 90° C. for 16 h. The POCl3 was evaporated and to the residue was added EtOAc (100 mL) and the solution was washed with a.q. NaHCO3 (80 mL) and H2O (80 mL). The EtOAc was removed under vacuum to give the desired compound (6.0 g, yield 85%). LCMS (m/z): 270.1 [M+H]+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:10][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH2:11][Br:12])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Methyl p-tolyl sulfone (24 g, 0.14 mol) in 550 ml CCl4 was heated to reflux temperature, N-bromosuccinimide (17.8 g, 0.14 mol) was added in portions and the mixture was refluxed for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to yield 4-methanesulfonylbenzyl bromide as a crystalline solid (32.9 g), 1H-NMR (CDCl3) δ 8.05 (d, 2H), 7.70 (d, 2H), 4.45 (s, 2H), 3.09 (s, 3H). To the crude product in water (200 ml) were added sodium sulfite (33.2 g, 264 mmol) and tetrabutylammonium bromide (0.41 g, 1.64 mmol), and the mixture was refluxed for 2 h. After cooling to room temperature the solution was extracted with ethyl acetate, the aqueous phase was then concentrated to half the volume and cooled. The precipitate was filtered off and dried under vacuum at 70° C. to yield sodium 4-methanesulfonyl-benzylsulfonate (33.3 g, quant.).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)=[O:21]
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.83 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.2 g (39 mmol) of trichloroacetyl chloride to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 50 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-propanol (2-PrOH) and stirred at room temperature overnight. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of an orange solid,mp 147-148° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.97 (dd, 1H), 7.30 (dd, 1H), 7.38 (dd, 1H), 7.52 (s, 5H), 7.65 (dd, 1H). 1H-NMR reveals the presence of a single isomer.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[C:18]=1[Cl:25]>CN(C=O)C>[Br:16][C:17]1[C:18]([Cl:25])=[C:19]([CH2:23][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1c(Br)cccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cccc(Br)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.21 g, 8.5 mmol) was dissolved in anhydrous DMF (50 mL), and then potassium carbonate (1.76 g, 12.7 mmol) and 1-bromo-3-(bromomethyl)-2-chlorobenzene (3.13 g, 11.0 mmol) in anhydrous DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was filtered, washed with water plus diethyl ether, and dried in vacuo to afford to 2-{[(3-bromo-2-chlorophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.28 g, 78% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 4.39 (s, 2H), 5.67 (s, 1H), 7.17 (t, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 2H); LRMS (ES+) m/z 345 (75%, M+1), 347 (100%, M+3), 349 (30%, M+5).
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC=CC=1.[CH3:16][C:17]1[O:18][C:19]([CH3:25])=[CH:20][C:21]=1[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH:2]1([N:8]([C:22]([C:21]2[CH:20]=[C:19]([CH3:25])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: ONC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C(=O)N(O)C2CCCCC2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.6 Parts of N-cyclohexylhydroxylamine hydrochloride is added to 300 parts of benzene; 20.2 parts of triethylamine is then introduced into the mixture. After stirring the mixture for 1 hour at room temperature, 15.9 parts of 2,5-dimethylfuran-3-carboxylic chloride is dripped in. The mixture is then stirred for a further hour and the precipitate is suction filtered, washed with water and then with petroleum ether, and dried. There is obtained 18.2 parts of N-cyclohexyl-2,5-dimethylfuran- 3-hydroxamic acid; m.p.: 135° - 137° C. ##SPC7##
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][NH:28][C:22]=2[CH:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[CH:42][CH:41]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc(N5CCN(C)CC5)cc4)c3cn2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine. LCMS (M+H)+=466.2.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].CO[Na].[C:13](OC)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][CH:2]1[O:9][C:24]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CCCCCCCCCCCC(=O)OC
Reactant: CC(O)CNCC(C)O
Agent: CC(=O)[O-]
Agent: CO[Na]
Agent: [Zn+2]
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 75 °C

Procedure:
In a first stage to a reactor, equipped with a distillation column, condenser, and graduated receiver, 199.8 g (1.5 mol) of diisopropanol amine (DIPA) and 7.5 g of CH3ONa (30% in methanol) were added and the batch heated to 75° C. 160.5 g (0.75 mol) of methyl laurate were added during 2 hours at 75° C. Temperature was gradually increased during 3 hours. Methanol has been removed at lower pressure 26,660 Pa) and at 120° C. and excess of DIPA has been removed at a pressure below 133 Pa and at 140° C. The so prepared amide looked as yellow fat (melting temperature of above 130° C). In a second stage 0.5 weight % of zinc acetate, based on the intermediate product after stage 1 were added and the batch was heated at 180° C. for 6 hours. Fraction distillation has been done at a pressure below 133 Pa. Three fractions were obtained: I) with boiling point <105° C.; amount above 5 weight %; mainly DIPA; II) with boiling point 105-145° C.; amount 50 weight %; amide acetal (purity 90%) and III) 45 weight %—distillation rest. The yield of amide acetal calculated on methyl laurate was 43%. Initial color and color stability during storage (on shelf) of an amide acetal prepared according to the invention and a comparative amide acetal prepared from nitriles have been evaluated. The amide acetal according to the invention shows a better initial color and better color stability than the amide acetal prepared from nitrites.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10](O)=[O:11])[N:7]=[N:6]1.S(Cl)(Cl)=O.[NH3:22]>>[CH:15]1[CH:14]=[C:13]([F:17])[C:3]([CH2:4][N:5]2[N:6]=[N:7][C:8]([C:10]([NH2:22])=[O:11])=[CH:9]2)=[C:2]([F:1])[CH:16]=1
Reactant: N
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C

Procedure:
A mixture of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (25 gms) and thionyl chloride (63.5 gms) were stirred at 80° C. and maintained for 3 hours. The reaction mass was cooled to 50° C. and excess thionyl chloride was distilled off. To this reaction mass toluene (25 ml) was charged twice and it was distilled off under vacuum it was followed by addition of toulene (175 ml) to get clear solution. Aqueous ammonia (100 ml) charged into reaction mass at room temperature and maintained for 2 hours. The reaction mass was filtered. 10% sodium carbonate solution was added to above solid and stirred for 30 minutes. The solid was filtered and washed with water and cyclohexane (50 ml). Dried the crude material in a vacuum oven at 70-80° C. for 10 hours. Yield: 23.00 gm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
To a solution of 2-bromo-5-fluoro-benzaldehyde (17.0 g, 83.7 mmol) in tetrahydrofuran (100 mL), cooled to 0° C. under nitrogen, was added methyl magnesium chloride solution (3M in tetrahydrofuran, 31.0 mL, 93.0 mmol, 1.1 eq.) dropwise over a 20 min period. The resulting solution was stirred at 0° C. for 45 min before quenching with aqueous ammonium chloride solution (1M, 17 mL). The resulting mixture was partitioned between pentane (300 mL) and water (100 mL). The organic phase was washed with brine (50 mL) and then dried over magnesium sulphate. This mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of toluene in pentane (50:50 to 100:0 by volume) to produce the title compound as a colourless oil (13.8 g, 75%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14][CH3:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.C([O-])(O)=[O:24].[Na+].OOS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:15])=[O:24])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CSc1nnc(Nc2ncc(Br)c(N[C@@H](CO)C(C)C)n2)[nH]1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 159 mg (0.41 mmol) of (R)-2-[5-bromo-2-(5-methylsulfanyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol in 4 ml of MeOH/water (4:1) is mixed with 80 mg (0.95 mmol) of NaHCO3 and 98 mg (0.95 mmol) of oxone. The reaction mixture is stirred for 2 hours at room temperature, then another 50 mg (0.5 mmol) of oxone is added, and it is stirred for 1 hour at 30° C. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation and purified by chromatography (methylene chloride-(methylene chloride/ethanol: 9/1); Flashmaster II). After the recrystallization, 45 mg (0.11 mmol, 27% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([OH:17])=O)[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:31][C:26]2([S:30][CH2:29][CH2:28][S:27]2)[CH2:25][NH:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:31][C:26]2([S:27][CH2:28][CH2:29][S:30]2)[CH2:25][N:24]1[C:15]([C:12]1[NH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][N:13]=1)=[O:17])=[O:22]
Reactant: O=C(O)c1nc(CCCc2ccccc2)c[nH]1
Reactant: COC(=O)[C@@H]1CC2(CN1)SCCS2
Agent: Br
Product: COC(=O)[C@@H]1CC2(CN1C(=O)c1ncc(CCCc3ccccc3)[nH]1)SCCS2

Procedure:
4-(3-Phenylpropyl)imidazole-2-carboxylic acid (13d) was coupled to 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester hydrobromide (Smith et. al., J. Med. Chem., 31, pp. 875-85 (1988)) by the method described for 23 to afford 140 mg (65%) as a yellow gum: 1H NMR (CDCl3) δ 7.34-7.15 (5H, m), 6.98-6.8 (1H, 3 s), 5.7-5.65 (0.5H, m), 5.2-5.1 (1H, m), 4.82-4.75 (0.5H, m), 4.4-4.35 (1H, m), 4.05 (1H, d), 3.75-3.7 (3H, 2 s), 3.4-3.3 (4H, m), 2.95-2.45 (8H, m), 2.05-1.95 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.ClC1C=CN=C2C=C(C3N=CN(C)C=3)SC=12.I[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:32]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CN(CCn1cc(I)cn1)C(=O)OC(C)(C)C
Agent: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Product: CN(CCn1cc(-c2cc3nccc(Cl)c3s2)cn1)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Starting from the chloride 2 and following the procedure described above for the synthesis of 175 (scheme 35, example 138), but replacing 4-iodo-1-methyl-1H-imidazole with tert-butyl 2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate, title compound 180 was obtained in 75% yield. LRMS (M+1) 393.1 (100%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH:27]([CH2:28][N:29]([C@@H:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[C:32]([O:31][C:30]([N:29]([CH2:28][CH:27]1[CH2:26][CH2:25][N:24]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:23][CH:22]1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=1)[C@@H:37]([C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2nc(Cl)[nH]c2c1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)[nH]c2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 313 mg of methyl 2-chloro-1H-benzimidazole-6-carboxylate and 100 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was stirred at 130° C. for 9 hours. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylate as a pale yellow solid. ESI+: 637
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:15])[CH:9]=[C:8]([Cl:16])[N:7]=1.Cl>C1COCC1>[Cl:16][C:8]1[N:7]=[C:6]([O:4][CH3:3])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:15])[CH:9]=1
Reactant: CO
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(Cl)cc(C)c1C(=O)O
Temperature: 70 °C
Yield: 120.5 %

Procedure:
To a suspension of 9.3 g (231 mmol, 60% w/w in mineral oil) NaH in THF (200 ml) was added a solution of 3.8 ml (93 mmol) Methanol in THF (200 ml) while the temperature was kept at 10-20° C. Subsequently a solution of 20.0 g (97 mmol) of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in THF (200 ml) was added and the RM was heated to 70° C. for 16 h. After cooling to RT the mixture was acidified with a 2M aq. HCl to pH 3-4 and was then extracted with EtOAc (2×600 ml). The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The obtained crude 22.6 g 6-chloro-2-methoxy-4-methyl-pyridine-3-carboxylic acid was used in subsequent reactions without further purification.