Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CO[C:17]1[C:25]2OC(C(O)=O)CC=2C=C[CH:18]=1.O[C:30]1C=CC=C2C=1C=C1C(=C2)C(=O)CCC1.C(Br)C#C.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH2:25]([O:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:30])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: O=C1CCCc2cc3c(O)cccc3cc21
Reactant: COc1cccc2c1OC(C(=O)O)C2
Reactant: COC(=O)C1Cc2cccc(O)c2O1
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cccc2c1OC(C(=O)OCC)C2

Procedure:
37.57 g (0.194 mol) of methyl 7-hydroxy-2,3-dihydro-benzofuran-2-carboxylate [prepared from the known 7-methoxy-2,3-dihydro-benzofuran-2-carboxylic acid, G. Goldenberg et al., Chim. Ther. 8 (3), 1973, 259-270] and 32.85 g (0.213 mol) of propargyl bromide (80% in toluene) are refluxed in the presence of 29.49 g (0.213 mol) of K2CO3 in 194 ml of dry butanone for 5 h. After cooling, the precipitate is filtered off and washed well with acetone, and the filtrate is evaporated. The residue is taken up in 200 ml of CH2Cl2, shaken twice with 10% strength NaOH solution, dried over Na2SO4 and evaporated. The residue is flash chromatographed on silica gel (eluent: petroleum ether/acetone 5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[C:29]([O:33][CH2:34][CH2:35][O:36][NH2:37])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][CH2:34][CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CC(C)(C)OCCON
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOCCOC(C)(C)C)c(=O)n(C)c1=O
Temperature: 100 °C

Procedure:
Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551. found, 551.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:18][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: [Cl-]
Reactant: OC1Cc2cc(F)ccc2Sc2ccccc21
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)CC(Cl)c1ccccc1S2

Procedure:
21.2 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 110 ml of benzene and 7.9 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C (2 hours). The precipitate is filtered off and washed with benzene. The filtrate is evaporated under reduced pressure. There is obtained 10-chloro-2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin as pink crystals which melt at 90°-92° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc2c(c1)CC(Nc1nc3ccccc3[nH]1)C2

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-aminoindane by Procedure A (15 min at 150° C.). The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 246-249° C.). MS(ES+) m/z 250 ([M+1]+, 100). 1NMR (DMSO-d6) δ 2.91 (dd, 2H), 3.29 (dd, 2H), 4.35 (m, 1H), 6.80-6.92 (m, 3H), 7.10-7.17 (m, 4H), 7.22-7.25 (m, 2H), 10.60 (s, 1H).
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH2:12]([SH:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH2:12]([S:14][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Reactant: CCS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(CC(=O)O)C(=O)C(=O)O

Procedure:
In 20 ml of dichloromethane was suspended 1.00 g of 3-bromo-2-oxoglutaric acid. To the suspension was added 0.33 ml of ethane thiol under ice-cooling and stirring, to which was added 1.83 ml of triethylamine. The reaction solution was stirred at room temperature for 3 hours, then the solvent was evaporated off. The residue was shaken with a mixture of ethyl acetate and 1N-HCl. The ethyl acetate layer was taken, washed with water and dried (Na2SO4). The solvent was evaporated off to give 0.82 g of 3-ethylthio-2-oxoglutaric acid as pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1)([CH3:3])[CH3:2].CN.[CH3:33][N:34](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][NH:34][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:14]
Reactant: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C
Yield: 42.7 %

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (44.0 mg) was prepared by following General Procedure F starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 451; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, m), 8.10 (1H, m), 7.92 (1H, m), 7.75-7.68 (2H, m), 7.37-7.35 (1H, m), 5.17-5.12 (1H, m), 2.82-2.80 (3H, s), 1.58-1.57 (6H, d), 2 —NH proton signals were not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[N:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[N:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:32])=[O:31]
Reactant: Nc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(NS(=O)(=O)CCCCl)c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Amino-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (100 mg, 0.28 mmol) was dissolved in DMF (5 mL) and 3-chloro-propane-1-sulfonyl chloride (1 eq, 35 □L) was added followed by triethylamine (2 eq, 80 □L). The reaction mixture was stirred at RT for 3 hours and then diluted with EtOAc and extracted with water. The organic layer was dried and concentrated to give brown oil, which was used without further purification.
Reaction SMILES: [Li]CC[CH2:4][CH3:5].Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9](Br)=[C:10]([Br:12])[N:11]=1.BrCC.CN([CH:28]=[O:29])C>C1COCC1>[Br:12][C:10]1[N:11]=[C:7]([CH2:4][CH3:5])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[CH:28]=[O:29]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: [Li]CCCC
Reactant: CN(C)C=O
Solvent: CCBr
Solvent: C1CCOC1
Product: CCc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
n-BuLi (1.42 mL of a 1.6 M solution in hexanes, 2.24 mmol) was added dropwise to a −78° C. solution of 2,4,5-tribromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.98 g, 2.24 mmol) in THF (46 mL). The reaction mixture was stirred for 30 min and bromoethane (0.17 mL, 2.24 mmol) was added dropwise. The solution was stirred for 4 h at RT, cooled to −78° C., and n-BuLi (1.42 mL of a 1.6 M solution in hexanes, 2.24 mmol) was added dropwise. After 30 mins, DMF (2 mL, 23.9 mmol) was added. The reaction mixture was allowed to warm to RT, quenched by addition of sat'd NH4Cl and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-70% EtOAc/hex) to afford the title compound (0.16 g, 22%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.69 (s, 1H), 5.70 (s, 2H), 3.50-3.60 (m, 2H), 2.79 (q, J=7.51 Hz, 2H), 1.35 (t, J=7.56 Hz, 3H), 0.78-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][NH:42]2)=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2.[C:54]([O:58][C:59](=[O:68])[CH2:60][C@H:61]1[CH2:64][C@H:63]([C:65](O)=[O:66])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:38][C:39]([C@H:41]2[C:50]3[C:45](=[CH:46][C:47]([CH2:51][O:52][CH3:53])=[CH:48][CH:49]=3)[CH2:44][CH2:43][N:42]2[C:65]([C@H:63]2[CH2:62][C@H:61]([CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:68])[CH2:64]2)=[O:66])=[O:40])[CH:30]=[C:31]2[C:35]=1[C:34]([CH3:37])([CH3:36])[CH2:33][CH2:32]2
Reactant: COCc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (49.9 mg, 0.13 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (50 mg, 0.12 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (26.9 mg, 0.13 mmol) and DIEA (0.024 mL, 0.13 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (74.0 mg, 0.128 mmol, 107%) as a white solid.
Reaction SMILES: [NH2:1][C@@:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C@@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[C:18]1([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:30]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C@:2]1([NH:1][C:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:30][C:29]=3[C:28]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:37])[CH2:6][C@@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2
Reactant: CO[C@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Yield: 67.4 %

Procedure:
A solution of [(1R*,2S*,4S*)-2-amino-2-(2-fluorophenyl)-4-methoxycyclopentanyl]methanol (225 mg) and fluorenylmethyloxycarbonyl isothiocyanate (316 mg) in dichloromethane (18 mL) was stirred at room temperature for three days. The reaction solution was purified by silica gel column chromatography to obtain the title compound (330 mg).
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].[C:31](O)(=O)[C:32](O)=O.[C:37](O)(=O)CC>>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:31]=[CH2:32])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH2:27][CH2:28][CH2:29][CH3:37]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: CCC(=O)O
Reactant: O=C(O)C(=O)O
Product: C=CC1CN(c2ncc(C(=O)N(CCCCC)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A mixture of 2.41 g (5 mmol) of a compound II (R1 =CH3 ; R2, R3, R5 =H; R4 =CH3CHCH2CH(CH3)2 ; R6 =F), 270 mg (3 mmol) of oxalic acid and 4.2 ml of propionic acid was stirred at 70° for 2 hours and then worked up as in Example 5. 1.50 g (62.3% yield) of the compound I (R1 =CH3 ; R2, R3, R5 =H ; R4 =CH3CHCH2CH(CH3)2 ; R6 =F) were obtained, melting point 135°-137°.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7](=O)/[C:8](=[N:33]/[O:34][CH3:35])/[C:9]([NH:11][CH:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19][S:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10].O1CCCC1.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[CH3:35][O:34]/[N:33]=[C:8](\[C:9]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19][S:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10])/[C:7]1[N:1]=[C:2]([NH2:4])[S:3][CH:6]=1
Reactant: NC(N)=S
Reactant: CO/N=C(/C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
25.0 g (0.3289 moles) of thiourea was dissolved in 160 ml of demineralised water. This solution was added to a mixture containing 7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acid in methylene chloride, as obtained from Step C 240 ml of tetrahydrofuran (THF) over a period of 30 mins. The reaction mixture was stirred for 2 hrs at 5-10° C. The pH of the solution was adjusted to 5.0 with aqueous sodium bicarbonate solution.
Reaction SMILES: [CH3:1][C:2]([C:6]([OH:8])=[O:7])([CH2:4][OH:5])[NH2:3].O=S(Cl)Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:2]([NH2:3])([CH3:1])[CH2:4][OH:5]
Reactant: CO
Reactant: CC(N)(CO)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(N)CO
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A strring solution of α-methyl-DL-Serine (1 g, 8.39 mmol) in MeOH (40 mL) in a flame dried round bottom flask under an inert atmosphere was cooled to 0° C. and SOCl2 (1.84 mL, 25.19 mmol) was slowly added. After addition of the SOCl2 was complete, the reaction mixture was stirred 12 h at rt and then concentrated in vacuo to a white solid that was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=CC)[CH3:2].C(O)(C(F)(F)F)=[O:22].O=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[O:22])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC=CC(CC(=O)OCC)c1cnc2ccccc2c1
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CC(C=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 22-3 (1.0 g, 3.7 mmol), TFA (0.06 mL, 3.9 mmol), and sudan red (0.5 mg) in anhydrous CH2Cl2 (50 mL) was cooled to −78° and treated with O3 until the sudan red color disappeared (5 min). Solid Ph3P (1.4 g, 5.6 mmol) was added and the solution warmed to room temperature. After 30 min., the solution was washed with sat. NaHCO3, dried, filtered, and evaporated. Chromatography on silica gel (10% acetone/EtOAc) afforded 22-4 as colorless glass.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:1])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 967 %

Procedure:
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0° C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1)[CH3:18]
Reactant: O=C(Nc1ccccc1)c1cncc(Br)c1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cncc(C(=O)Nc3ccccc3)c2)cc1

Procedure:
74 g (222 mmol) of 5-bromo-N-phenylpyridine-3-carboxamide and 40 g (266 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 68 g (87% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:18]=3)=[CH:12][CH:13]=[C:8]2[N:7]=[N:6]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[ClH:1].[Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)=[CH:12][CH:13]=[C:8]2[N:7]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4nnn(Cc5c(F)ccc(F)c5Cl)c4n3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Fc1ccc(F)c(Cn2nnc3ccc(-c4cnn(C5CCNCC5)c4)nc32)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of Example 166 (0.240 g, 0.453 mmol) in dichloromethane (3 ml) cooled to 0° C., TFA (0.1 ml) was added and warmed to RT. After 2 h, the reaction mixture was poured in ice water and pH was adjusted to call with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The residue was dissolved in THF (1 ml), ether saturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was filtered and washed with ether and dried under vacuum to afford the title compound as an off-white solid (0.090 g, 43%). M.P.: 85-87° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.48 (d, J=1.5 Hz, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.60 (dt, J=13.8, 4.8 Hz, 1H), 7.45 (dt, J=13.4, 4.2 Hz, 1H), 6.01 (s, 2H), 4.29 (m, 1H), 3.07 (d, J=12.4 Hz, 2H), 2.63 (m, 2H), 1.98 (m, 2H), 1.85 (m, 2H). MS (m/z):: 429.69 (M+-HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[C:23]([Br:25])[C:22]([NH2:26])=[C:21]([Br:27])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:34]O>>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][S:18]([C:19]3[CH:24]=[C:23]([Br:25])[C:22]([NH2:26])=[C:21]([Br:27])[CH:20]=3)=[O:34])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: OO
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1cc(Br)c(N)c(Br)c1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCS(=O)c1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[2-(4-amino-3,5-dibromophenylthio)-ethyl]-methylamine and 30% hydrogen peroxide (in glacial acetic acid) analogously to Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]COC)=[CH:4][C:3]=1[CH2:12][C:13]#N.[OH-:15].[Na+].O.[CH2:18]([OH:20])[CH3:19]>>[C:18]([O:15][CH2:13][CH2:12][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:20])[CH3:19]
Reactant: CCO
Reactant: COCOc1ccc(Cl)c(CC#N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCc1cc(O)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of [2-chloro-5-(methoxymethoxy)phenyl]acetonitrile (2.60 g; 12.3 mmol), sodium hydroxide (2.46 g; 61.5 mmol), water (10.4 ml) and ethanol (33.8 ml) was stirred at 80° C. for 3 hours. After cooling, the solvent was evaporated under reduced pressure. To the residue was added water and 2N-aqueous hydrochloric acid to become acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. To the residue, were added concentrated hydrochloric acid (0.65 ml) and ethanol (15 ml). The mixture was stirred at 80° C. for 8 hours. After cooling, the reaction solution was condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give [2-chloro-5-hydroxyphenyl]ethyl acetate as colorless oil (0.69 g; 26%).
Reaction SMILES: Cl[C:2]1[C:3]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4][S:5][N:6]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CO>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[C:3]([O:7][CH2:8][C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)=[N:4][S:5][N:6]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nsnc1OCc1ccncc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(c3nsnc3OCc3ccncc3)CC2)cc1
Temperature: 70 °C
Yield: 9 %

Procedure:
4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (50 mg, 0.22 mmol) was dissolved in 200 μL of DMF along with 1-phenylpiperazine (75 μL, 0.49 mmol). The reaction was heated to 70° C. overnight. The reaction mixture was diluted with methanol to a volume of 2 mL and the reaction mixture was purified by reverse phase chromatography, affording 1-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine (7 mg). 1H NMR (DMSO-d6) δ 8.62 (d, 2H), 7.46 (d, 2H), 7.23 (t, 2H), 7.01 (d, 2H), 6.82 (t, 1H), 5.58 (s, 2H), 3.64 (m, 4H), 3.23 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=[CH:13][C:12]=1[N+:24]([O-])=O.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[NH2:24][C:12]1[CH:13]=[N:14][N:15]([CH2:16][CH2:17][O:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:11]=1[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:7]#[N:8]
Reactant: COc1ccc(C#N)cc1-c1c([N+](=O)[O-])cnn1CCOC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C#N)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 86.7 %

Procedure:
To a solution of 4-methoxy-3-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)benzonitrile (900 mg, 2.4 mmol) in 25 mL ethanol was added 50 mL water, ammonium chloride (636 mg, 12 mmol), and iron powder (806 mg, 14 mmol). The reaction mixture was stirred at 75° C. for 6 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 717 mg (84%) of 3-(4-amino-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)-4-methoxybenzonitrile, which was carried forward without purification. LCMS (ESI) m+H=375.1.