Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:11][CH2:10][CH2:9]1.C=O.[C:27]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:27])[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc2c(cc1C)CCNC2C1(c2ccccc2Cl)CCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccc2Cl)CCC1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
A mixture of the oxalate salt of 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline (4.42 g prepared as described in Example RC12), methanol (87 ml) and 37-40% aqueous formaldehyde solution (5.1 ml) was cooled to 10° C. and sodium cyanoborohydride (2.64 g) was added. After 10 minutes the mixture was allowed to warm to ambient temperature and was stirred for 24 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and dilute aqueous sodium hydroxide solution. The organic phase was washed with aqueous ammonia solution, then dried and concentrated to yield 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline (3.3 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([N:29]3[CH2:38][CH2:37][C:32]4(OCC[O:33]4)[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[OH-].[Na+]>Cl>[O:33]=[C:32]1[CH2:37][CH2:38][N:29]([C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:5]3([N:8]4[CH2:13][CH2:12][N:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH2:10][CH2:9]4)[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]3)[CH:21]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: CC1CCC(c2cccc(NC(=O)N3CCC4(CC3)OCCO4)c2)(N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CCC(c2cccc(NC(=O)N3CCC(=O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Reaction time: 1 h

Procedure:
A solution of N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)-cyclohexyl]phenyl]-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxamide (cis isomer) (34 mg, 0.066 mmol) was dissolved in 4 mL of 6N HCl and the clear homogeneous solution was allowed to stand for 1 h at room temperature. The reaction mixture was made basic with 1N NaOH, extracted with CH2Cl2, dried (Na2SO4) and concentrated to give the crude ketone. The residue was triturated with 30% EtOAc/hexanes to yield colorless crystals of 4-(oxo)-N-[3-[4-methyl-1-(4-phenyl-1-pipera-zinyl)-cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer). mp=~173° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[C:17]([CH2:18]Br)=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[C-:22]#[N:23].[Na+]>>[Br:1][C:2]1[O:3][C:4]2[C:17]([CH2:18][C:22]#[N:23])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c2oc(Br)c(-c3ccccc3F)c12
Agent: [Na+]
Product: COc1ccc(CC#N)c2oc(Br)c(-c3ccccc3F)c12

Procedure:
Using the method of Example 17, 2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran is reacted with sodium cyanide to provide 2-bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran as a brown solid after isolation by column chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28]([S:29][C:30]2[CH:35]=[C:34]3[O:36][CH2:37][O:38][C:33]3=[CH:32][C:31]=2I)=[N:27][C:21]2[C:22]([NH2:26])=[N:23][CH:24]=[N:25][C:20]1=2)[CH3:14].C([O-])(O)=O.[Na+].CN(C=O)C>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.O>[NH2:26][C:22]1[N:23]=[CH:24][N:25]=[C:20]2[C:21]=1[N:27]=[C:28]([S:29][C:30]1[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:32][C:33]3[O:38][CH2:37][O:36][C:34]=3[CH:35]=1)[N:19]2[CH2:18][CH2:17][CH2:16][NH:15][CH:13]([CH3:12])[CH3:14]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 65.5 %

Procedure:
4-Formylphenylboronic acid (13 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 1H NMR (500 MHz, MeOH-d4) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.13 (s, 2H), 4.05 (t, J=6.8 Hz, 2H), 2.99 (septet, J=6.4 Hz, 1H), 2.62 (t, J=6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0, 117.7, 115.0, 110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H27N6O3S, 491.1865; found. 491.1877; HPLC: method A Rt=6.23, method B Rt=6.83.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(Cl)c(Cl)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(Cl)c(Cl)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dichloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[C:8]2[C:13]([CH:14]=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>CCOCC.CO>[CH:19]1[C:20]2[C:15](=[CH:14][C:13]3[C:8]([C:7]=2[B:25]([OH:26])[OH:24])=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CO
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
sec-BuLi (4.3 mL, 6.0 mmol, 1.4M solution in cyclohexane) was added dropwise to a solution of 9-bromoanthracene (1.29 g, 5.0 mmol) in Et2O (20 mL) at 0° C. under N2. The reaction was held at 0° C. for 15 minutes then warmed to rt and stirred an additional 45 minutes. Triisopropylborate (1.5 mL, 6.5 mmol) was added and the reaction was stirred at rt for 18 h. Concentrated HCl (1.0 mL) and MeOH (1.0 mL) was added and the reaction was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with H2O, sat. NaHCO3 (aq.), brine, and then dried over Na2SO4. Filtration and concentration gave 1.05 g of 9-anthraceneboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]C1C=C(I)C=CC=1>>[Br:24][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:19]
Reactant: Brc1cccc(I)c1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: O=C(O)Cc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 3-bromoiodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[O:31]1[C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:36]([C:35]3[O:31][N:32]=[CH:33][CH:34]=3)=[O:37])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccno1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)c3ccno3)ccc2O1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and isoxazole-5-carbonyl chloride as a yellow oil (72%). M− (ESI): 511.5; M+ (ESI): 513.1. HPLC, Rt: 5.38 min (Purity: 99.1%).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CC(C)CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCC(C)C)cc1

Procedure:
A mixture of 5 g. of 15-methylhexadecyl bromide and 5.2 g. of ethyl 4-aminobenzoate in 50 ml. hexamethylphosphoramide is heated for 17 hours at 120° C. The cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered, washed with 100 ml. of 50% ethanol, dried, and crystallized from ethanol to yield a colorless crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:42])([CH3:41])[C:39]#[N:40])=[CH:34][CH:33]=1>C(Cl)Cl>[C:39]([C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:37][CH:36]=1)([CH3:42])[CH3:41])#[N:40]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: CC(C)(C#N)c1ccc(CN)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3ccc(F)c(F)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
(6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (42 mg, 0.2 mmol) prepared according to scheme 2 is dissolved in CH2Cl2 (2 mL). Triethylamine (83 μL, 0.6 mmol) is added, followed by pivaloyl chloride (25 μL, 0.2 mmol). After 30 minutes, 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (35 mg, 0.2 mmol) prepared according to scheme 18 is added dissolved in 1 mL of CH2Cl2. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 40% to 60% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (17 mg, 0.05 mmol, 25%). MS (ESI) (M+1) 383.3. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.65 (s, 6H) 2.30 (s, 3H) 4.29 (d, J=5.47 Hz, 2H) 5.09 (s, 2H) 7.19-7.31 (m, 3H) 7.32-7.35 (m, 1H) 7.47 (dd, J=8.98, 3.91 Hz, 1H) 8.22 (s, 1H) 8.66-8.74 (m, 1H).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:24][NH2:25]>>[OH:1][CH:2]([CH2:23][NH:25][CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Reactant: CN
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
Reaction of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman with methylamine by an analogous method to that described in Example 2 gave 7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-4-phenylchroman isolated as its hydrochloride salt, (57%), m.p. 182°-183°.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:23])[OH:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[OH:23])[NH:18][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
γ-Benzyl-L-glutamyl-L-proline benzylester hydrochloride (2.30 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mole) was added thereto at -30 ° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The solution was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 55 aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice), and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-γ-benzyl-L-glutamyl-L-proline benzylester (yield: 2.61 g, 92.4%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1CO
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-Bromo-2-methylbenzoic acid (11.1 g, 51.6 mmol) is dissolved in anhydrous THF (11.2 mL). The solution is cooled to 0-5° C. and a 1 M solution of BH3. THF (103 mL) is added to the mixture. The solution is left stirring 3 h at room temperature. Cold water is then added (20 mL) and the reaction mixture is washed with a saturated solution of NaHCO3 (120 mL). The aqueous phase is extracted with diethyl ether (3×300 mL) and the combined organic phases washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The resulting oil is purified by flash-chromatography, eluting with hexane/EtOAc from 95:5 to 70:30, to provide the expected product (4-Bromo-2-methylphenyl)methanol (10.4 g, 100%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=O)[CH3:14])[O:12][C:7]=2[CH:6]=1.Cl.[NH2:31][OH:32].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13](=[N:31][OH:32])[CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CC(=O)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
7-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-acetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 93) (0.3 g) obtained in Example 15 was dissolved in ethanol (10 ml), and hydroxylamine hydrochloride (0.1 g) and 1N-sodium hydroxide (0.8 ml) were added, followed by stirring at 90° C. for 2 hours. The reaction mixture was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=2/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: Cc1nc(C)c(C=O)s1
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-(E)-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 135; 116 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 36 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried, filtered, evaporated and chromatographed (60% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (101 mg, 84% yield) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(S(N)(=O)=O)CC3)ccc2n1CC1CC1

Procedure:
The mixture of 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-[(piperidin-4-ylmethane)sulfonyl]-1,3-benzodiazole (STEP D of Example 5, 25 mg, 0.062 mmol), sulfamide (15 mg, 0.16 mmol)and 1,4-dioxane was refluxed for 6 h. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate (20 mL) and water (30 mL). The organic layer was washed with water (20 mL) and brine (15 mL), dried over magnesium sulfate. The crude product (27 mg) was purified by prep LC-MS(“process A”).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
4'-hydroxy 4-biphenylcarboxylic acid (5.0 g) was added to a stirred suspension of sodium hydride (60% w/w dispersion in mineral oil, 2.34 g) in dry dimethylformamide (45 ml) whilst maintaining the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at 10° C. for 20 minutes. A solution of benzyl bromide (8.4 g) in dry dimethylformamide (10 ml) was added over a period of 10 minutes. The reaction mixture was stirred at 70° C. for 2 hours and the mixture was then poured into cold water (900 ml) to precipitate a solid. The solid was collected by filtration, washed with water (3×200 ml) and added to a mixture of 2M aqueous sodium hydroxide solution (100 ml) and ethanol (100 ml). The mixture was stirred at 100° C. for 12 hours. The ethanol was removed by evaporation and the aqueous residue taken to pH 1.0 by the addition of 12M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, washed with water (3×100 ml), ethyl acetate (3×100 ml) and dried to give 4'-benzyloxy-4-biphenylcarboxylic acid (100% yield) as a colourless solid, m.p. >300° C.; m/z 304 (M).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
5.2 g (14.0 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 2.1 g (2.1 mmol, 1.2 eq.) of cyclopentanecarbonyl chloride were reacted according to General Method 3A. Yield: 4.8 g (96% of theory)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:7]1=[O:30].O>CN(C)C=O>[C:16]([O:15][C:13]([N:11]1[CH2:12][C@@H:6]([N:1]=[N+:2]=[N-:3])[C:7](=[O:30])[N:8]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:9][C@@H:10]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium azide (0.841 g, 12.9 mmol) was added to a solution of tert-butyl 6-bromo-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.609 g, 1.43 mmol) in N,N-dimethylforamide (10 mL) and heated to 70° C. After 1 h, the mixture was allowed to cool to ambient temperature and water was added. The mixture was extracted with ethyl acetate, washed with water (3×), saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (20% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave 170 mg of the trans isomer and 24 mg of the cis isomer. MS 386 (M+1).