Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1

Procedure:
To a flask containing N-phenyl-o-phenylenediamine (9.21 g, 50 mmol) and 4-bromobenzaldehyde (9.25 g, 50 mmol) was added 50 mL of 20-methoxyethanol. After the mixture was refluxed for 48 h, the volatile was removed under vacuum and the residue was extracted with CH2Cl2. The organic extract was washed with brine, dried over anhydrous MgSO4, filtered and pumped dry. The crude product was purified by column chromatography using a mixture of CH2Cl2 and n-hexane (1:1 by vol.) as the eluent. Analytically pure 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole was isolated as a white solid in 72% (9.77 g) yield. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, 1 H, J=8.0 Hz), 7.35-7.29 (m, 4 H), 7.24-7.20 (m, 1 H), 7.15-7.02 (m, 7 H). MS (FAB): m/z 348.9 (M+). Anal. calcd. for C19H13BrN2: C, 65.35; H, 3.75; N, 8.02. Found: C, 65.22; H, 3.78; N, 8.01.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[ClH:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Agent: Cl
Solvent: CCO
Product: Brc1cccc(Nc2ncnc3[nH]c4ccccc4c23)c1
Yield: 66 %

Procedure:
4-Chloroindolo[2,3-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated under reflux for 2 h. The solids are collected by suction filtration, washed with ethanol and dried to give 4-(3-bromoanilino)indolo[2,3-d]pyrimidine hydrochloride (248 mg, 73%). 1H NMR (DMSO) δ1H, s) , 9.02 (1H, s),8.51 (1H, s), 8.42 (1H, d, J=7.7 Hz), 8.08 (1H, t, J=1.9 Hz), 7.82 (1H, d, J 8.0 Hz), 7.53 (1H, d, J=7.9 Hz), 7.46 (1H, dt, Jd=1.0 Hz, Jt=7.6 Hz), 7.36-7.27 (3H, m).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[CH:18]>CCN(CC)CC.[Cu]I>[CH:19]1([C:17]#[C:18][C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:8])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(OCC1CCCCC1)c1ccc(Br)o1
Reactant: C#CC1CCCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(OCC1CCCCC1)c1ccc(C#CC2CCCCC2)o1
Reaction time: 8 h

Procedure:
A mixture of cyclohexylmethyl 5-bromofuran-2-carboxylate (0.63 g, 2.19 mmol) and ethynylcyclohexane (0.32 g, 2.96 mmol) in Et3N (10 mL) was degassed by bubbling Ar. CuI (0.023 g, 0.119 mmol) and PdCl2(Ph3P)2 (0.0412 g, 0.0587 mmol) were added and the reaction mixture was degassed by alternating vac/Ar three 3 times. The reaction mixture was stirred at +70° C. under Ar overnight and concentrated under reduced pressure. The residue was partitioned between hexanes and aqueous NH4Cl (25%) and aqueous layer was extracted twice with hexanes. Combined organic layers were washed with brine, treated with activated charcoal and dried over anhydrous MgSO4. Concentration under reduced pressure gave cyclohexylmethyl 5-(cyclohexylethynyl)furan-2-carboxylate as an orange solid which was used directly in the next step without additional purification. Yield (0.75 g, quant.); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=3.9 Hz, 1H), 6.50 (d, J=3.9 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 1.56-2.66 (m, 1H), 1.63-1.84 (m, 9H), 1.42-1.60 (m, 4H), 1.10-1.40 (m, 6H), 0.96-1.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:20]=[CH:19][C:12]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:20]=[CH:19][C:12]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CS(=O)(=O)NCc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2ccc(CNS(C)(=O)=O)cc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
219 mg N-[4-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide (prepared in Example 33) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (173 mg, 45% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].N>>[C:11]([NH:15][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)CC1CCCCC1
Reactant: CC(C)(C)N
Agent: N
Product: CC(C)(C)NCCC1CCCCC1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with cyclohexylacetic acid and t-butylamine. m/e (DCI/NH3) 184 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3CC(C)(C)C([O-])=O)[N:10]=2)[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:35]CC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([OH:35])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:2]=1
Reactant: C1CCOC1
Reactant: CC(C)(Cc1cccc2nc(C#Cc3cccnc3)ccc12)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Oc1cccc2nc(C#Cc3cccnc3)ccc12
Yield: 29 %

Procedure:
2-(Pyridine-3-ylethynyl)quinoline-5-ol (8.5 mg, 29%) was prepared as a yellow solid according to the same method as described in Example 16 except that 2-(pyridine-3-ylethynyl)quinoline-5-ylpivalate (40 mg, 0.121 mmol), LiAlH4 (0.3 mL, 1.0 M in THF), and THF (2.0 mL) were used.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([CH:24]=[O:25])=[C:9]1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:15]=2)[C:10]([CH:24]([OH:25])[CH3:29])=[C:9]1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C=O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)c1c(C(C)O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
General Procedure C. To a −78° C. solution of (1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxaldehyde (Compound 13, 200 mg, 0.55 mmol) in THF (5 mL) was added MeMgBr (3 M solution in THF, 1 mL, 3 mmol). The solution was stirred between −78° C. and −10° C. for 4 h, and then the reaction was quenched at −78° C. by adding EtOAc (2 mL) and water (5 mL). The mixture was warmed to room temperature and diluted with EtOAc (50 mL). The reaction was quickly washed with ice cold aqueous NH4Cl (5 mL), and brine (10 mL), and dried (Na2SO4), and the solvent was removed under vacuum to give 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanol as a mixture of two diastereomers that were used directly in the next step without further purification or characterization. Thus, crude 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanol (200 mg, 0.51 mmol) was oxidized to 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanone (Compound 14) by General Procedure B.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[C:17](=[O:18])[O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(O)(=O)C>[C:15]([NH:14][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17](=[O:18])[CH3:25])(=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC(c2ccccc2)N=C1CCCNC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)C(CCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-benzamidopropyl)-2-phenyl-5-oxazolone (1.0 g, 3.1 m.mol), 4-dimethylaminopyridine (0.016 g), acetic anhydride (0.62 ml) and triethylamine (0.62 ml) was stirred for one hour. Acetic acid (4.7 ml) was added and the solution was set aside overnight and evaporated to dryness. The residue was dissolved in chloroform and washed with dilute NaOH, dilute HCl and then dried over MgSO4. Concentration gave the crude product which could be purified by dry-column chromatography on alumina with ethyl acetate as solvent to give 3,6-dibenzamidohexan-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][CH2:16][CH2:15][N:14]=[C:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH2:12]1.[BH4-].[Na+].[C:29](OC(=O)C)(=[O:31])[CH3:30].CCN(C(C)C)C(C)C>C(#N)C.O.C(O)C>[C:29]([N:14]1[CH:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH2:12][CH:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[S:17][CH2:16][CH2:15]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)N(C(C)=O)CCS2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (187 mg, 0.5 mmol), prepared as in Reference 5, was combined with absolute ethanol (5 mL) and sodium borohydride (20 mg, 0.526 mmol) and the mixture was warmed on a hot plate to form a solution. The progress of the reaction was followed by analytical HPLC and LCMS and when complete (5 hours) acetic anhydride (1.5 ml. 30 eq) and DIPEA (0.6 mmol, 0.1 mL) were added. The reaction was stirred at room temperature overnight. Product was isolated by preparative HPLC (RPC18 column, acetonitrile/water containing 0.1% HCl) to provide 3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one (25 mg). LCMS: MH+ 420.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:56]([F:55])([F:67])[F:68])(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 14 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-(trifluoromethyl)benzenesulfonyl chloride as starting materials in 14% yield. LCMS for C31H30ClF3N7O3S (M+H)+: m/z=672.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH2:32][CH:28]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CCC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Yield: 60 %

Procedure:
To a suspension of 60 mg (0.2 mmol) of 5-amino -1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acid and 80 mg of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of dry pyridine under nitrogen was added 140 mg (0.9 mmol) of DBU, and the suspension was heated at 95° C. for 22 h. The resulting orange solution was then evaporated to dryness, water was added to the residue, and the orange solid was collected and washed with methanol to give 50 mg (60%) of yellowish solid after drying in vac-oven, m.p. 240.3°-242-3° C. 1H NMR (TFA) δ: 9.8 (s, 1H), 9.14 (s, 1H), 8.77 (s, 1H), 5.78-5.55 (m, 1H), 4.76-4.12 (m, 5H), 2.9-2.65 (m, 2H), 1.65-1.2 (m, 4H). Anal. calcd. for C19H18F 2 N6O3 : C, 54.81; H, 4.36; N, 20.17. Found: C, 54.52; H, 4.44; N, 20.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[C:9]([NH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ccnc(N)c1
Solvent: CC(C)=O
Product: Cc1ccnc(NC(=S)NC(=O)c2ccccc2)c1

Procedure:
A solution of 2-amino-4-methylpyridine (1.08 g, 10 mmol) and benzoyl isothiocyanate (1.63 g, 10 mmol) in acetone ( 15 mL) was stirred at RT for 1.5 h. The precipitate formed was filtered and washed with acetone to afford 1 -benzoyl-3-[4-methylpyridin-2-yl]-thiourea as a solid. This material was stirred with 2 N NaOH solution (15 mL) at 110° C. for 1 h, then cooled to RT, and the precipitate formed was washed with water and dried to provide (4-methylpyridin-2-yl)-thiourea (0.90 g, 53%). MS m/z 168 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)c(OC)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(CO)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of methyl 5-bromo-2,4-dimethoxy-benzoate (5.137 g, 22.05 mmol) in tetrahydrofuran (60 mL) cooled to 0° C. was added lithium aluminum hydride (863 mg, 22.05 mmol) in several portions. At the end of addition, the reaction mixture was stirred at 0° C. for 15 min before the icebath was removed. The reaction was continued at room temperature for 48 h. It was cooled to 0° C. and water (˜5 mL) was carefully added to quench the excess lithium aluminum hydride. Sodium hydroxide (5% solution, 20 mL) was then added and the layers were separated after 2 h of stirring. The product was extracted with diethyl ether (2×100 mL). The organic layers were washed with sodium bicarbonate solution (1×10 mL), brine (1×10 mL) and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded (5-bromo-2,4-dimethoxy-phenyl)-methanol as off-white solids (3.743 g, 81%).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:10]([C:20](=[O:38])[N:21]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH3:22])=[CH:9][N:8]=1)=O>C(OCC)C.C1(C)C=CC=CC=1>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=1)[CH2:23][N:21]([CH3:22])[C:20](=[O:38])[C:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:12][C:7]([CH2:5][OH:4])=[N:8][CH:9]=1
Reactant: COC(=O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution of 9 mg (4 mmol) lithium borohydride in 0.5 ml diethyl ether was added a solution of 346 mg (0.678 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester in 0.6 ml toluene. The mixture was gradually heated to 100° C., whereby diethyl ether was distilled off. After heating for 2 h at 100° C. the resulting suspension was concentrated. The residue was treated with 5 ml of a 1 M aqueous solution of hydrochloric acid for 5 min. Basification with potassium carbonate was followed by extraction with tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Flash chromatography afforded 240 mg (73.4%) of the title compound as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.ClCCl.C([O-])(=O)C.[K+].Br[C:39]1[S:40][C:41]2[C:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)=[C:46]([C@H:55]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45]([CH3:66])=[CH:44][C:42]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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.O>[C:62]([O:61][C@@H:55]([C:46]1[C:45]([CH3:66])=[CH:44][C:42]2[N:43]=[C:39]([C:2]3[CH:3]=[C:4]4[CH:10]=[C:9]([CH3:11])[NH:8][C:5]4=[N:6][CH:7]=3)[S:40][C:41]=2[C:47]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57])([CH3:63])([CH3:64])[CH3:65]
Reactant: Cc1cc2cc(Br)cnc2[nH]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4[nH]c(C)cc4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (85 mg, 0.403 mmol) in dioxane (4 mL) was added bis(pinacolato)diboron (123 mg, 0.483 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (33 mg, 0.040 mmol), potassium acetate (120 mg, 1.21 mmol). The mixture was degassed and heated at 100° C. for 2 h. The mixture was cooled, and then added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol), K2CO3 (139 mg, 1.00 mmol) and water (1.3 mL, degassed). The reaction mixture was heated at 100° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C30H30ClN3O3S: 548.3 (M+H+); Found: 548.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH3:2].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[O-2].[O-2].[O-2].[Cr+6].CCOCC>[CH2:1]([O:3][C:4]([CH3:13])([CH3:14])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][CH:10]=[O:11])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)CCO
Agent: [Cr+6]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(C)(C)CCCC(C)CC=O
Reaction time: 4 h

Procedure:
A mixture of 1.9 of 7-ethoxy-3,7-dimethyloctan-1-ol and 10 ml. of pyridine is added to a suspension of 8.0 g. of chromium trioxide in 100 ml. of pyridine with stirring under nitrogen. After about 4 hours at room temperature, the reaction is poured into saturated sodium bicarbonate and worked up with ether followed by washing with 2N NaOH, water, 10% HCl, water and brine and evaporated under reduced pressure to dryness and then filtered with hexane to yield 7-ethoxy-3,7-dimethyloctan-1-al.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:35])([CH2:28][N:29]1[C:33](=[S:34])[NH:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[H-].[Na+].N#N.[CH3:40]I>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:35])([CH2:28][N:29]1[C:33]([S:34][CH3:40])=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([F:12])[F:11]
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3nn[nH]c3=S)c3ccc(F)cc3F)nc2)cc1
Reactant: CI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nnnn1CC(O)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Reaction time: 1 h

Procedure:
To a magnetically stirred mixture of 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile (100 mg, 0.199 mmol) in dry THF (1990 μL) was added sodium hydride (17.51 mg, 0.438 mmol) in a 10 mL vial under N2 atmosphere. The reaction mixture was stirred at 0° C. for 15 min at which point methyl iodide (12.44 μL, 0.199 mmol) was added via microsyringe. The reaction was allowed to continue stifling at 0° C. for 1 hour. At this point the reaction was quenched with water and allowed to stir, then removed from the ice bath and extracted with CH2Cl2 (3×). The combined organic layers were dried by passing through a phase separator and volatiles were removed under a gentle stream of N2. The resulting residue was loaded onto a pad of celite and purified (SiO2, 10-35% Ethyl Acetate/Hexanes over 8 min, 35% for 4 min) to give the title compound as an off white foamy solid (82 mg, 76%).