Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=2)[C:3]=1[CH2:16][C:17]([NH2:19])=[O:18].C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:8]=2)[C:3]=1[C:16]1[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=1[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: CN(C)Cc1ccc2c(CC(N)=O)c(Cl)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c(Cl)ccc2c1
Reaction time: 0.5 h

Procedure:
Activated 3 Å molecular sieve (50 mg) is added to a solution of 2-(2-Chloro-6-dimethylaminomethyl-naphthalen-1-yl)acetamide (54.6 mmol, 0.20 mmol) and (1-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (55.7 mg, 0.26 mmol) in dry THF (2.5 ml) under an atmosphere of argon. A solution of 1.0 M KOtBu in THF (0.59 ml, 0.59 mmol) is then added in one portion at RT. After 30 minutes at RT, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the organic solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 700:110:90) to afford the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.12 (s, 6H), 3.46 (s, 2H), 3.82 (s, 3H), 6.16 (d, J=8.8 Hz, 1H), 6.45-6.51 (m, 1H), 6.96-7.02 (m, 1H), 7.32-7.40 (m, 2H), 7.60-7.68 (m, 2H), 7.88 (s, 1H), 8.06 (d, J=10 Hz, 1H), 8.15 (s, 1H). ES+-MS: 445.5, 446.6 [M+H]+.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CS[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:25]4[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=4)[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CSc1ncc(C#N)cn1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (from Step 2 of Example 302, 200 mg, 0.415 mmol) in N,N-dimethylformamide (1 mL), was added 2-(methylthio)pyrimidine-5-carbonitrile (75 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol). The mixture was heated at 80° C. for 5 h. The mixture was added water, stirred at rt for 2 h, filtered and rinsed with water to give 6-bromo-4-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (162 mg, 80% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.38 (d, J=2.0 Hz, 1H), 8.17 (s, 1H), 7.73 (dd, J=8.9, 2.3 Hz, 1H), 7.10 (s, 1H), 6.59 (s, 1H), 5.10-5.01 (m, 1H), 4.25 (d, J=3.7 Hz, 1H), 4.09 (br. s., 1H), 3.85-3.74 (m, 2H), 3.61-3.46 (m, 5H), 1.28 (d, J=6.4 Hz, 2H); MS (ES+) m/z: 372.26 (M+H); LC retention time: 1.92 min (analytical HPLC Method H).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22](=[O:27])C(Cl)(Cl)Cl)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:28].[OH-].[Na+]>O1CCCC1>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:27])=[O:28])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Yield: 84 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 10a) (9.8 g, 22.8 mmol) in tetrahydrofuran (160 ml) was added water (160 ml) and sodium hydroxide (4.5 g, 114 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MS (ca. 60 min). Approximately half of the solvents were evaporated in vacuo and the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 6.29 g (84%) of 8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid as white solid. LC/MS (method 4): Rt=1.14 min; m/z=329.26 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([CH2:18][C:19]([OH:21])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(Cl)CCl.OC1C2N=NNC=2C=CC=1>ClCCl>[O:25]1[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH2:18][C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)O
Reactant: C1COCCN1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3 g (10.30 mmol) of [(3S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]acetic acid in 100 mL of dichloromethane, there are added dropwise 1.10 mL (11.32 mmol) of morpholine, still dropwise 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of EDC and 1.70 g (1.68 mmol) of HOBt (hydroxybenzotriazole). The batch is stirred at ambient temperature for 15 hours. The reaction mixture is then diluted with dichloromethane, successively washed with 1M HCl solution, saturated aqueous NaHCO3 solution and then brine until neutral. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and methanol as eluants, the title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH3:28][N:29]1[C:38]2[NH:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][CH2:33][C:32]=2[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:33][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[C:38]=4[NH:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]3=4)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 5 %

Procedure:
4-{4-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (139 mg, 0.37 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (75 mg, 0.37 mmol) were dissolved in dichloromethane (5 ml) and DIEA (0.195 ml, 1.11 mmol). WSCD (93 mg, 0.48 mmol) and DMAP (9 mg, 0.07 mmol) were added and the mixture was heated at reflux for 3 days, then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (11 mg, 5%).
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1)=[O:12])=[O:8].Cl.C1COCC1.C(Cl)[Cl:40]>O1CCOCC1>[ClH:40].[NH2:20][C@@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:11](=[O:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:28]=[CH:29][CH:30]=[C:4]([C:3]([F:32])([F:31])[F:2])[CH:5]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 20 h

Procedure:
tert-Butyl cis-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate hydrochloride salt (350 mg, 0.79 mmol, 1 eq) was dissolved in dioxane (5 mL) at room temperature then 4N HCl (1.97 mL, 7.9 mmol, 10 eq) was added. Stirred for 20 hours. The reaction was stripped 4 times from 1:1 THF/methylene chloride (20 mL) to give N-(2-(cis-4-amino-cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide hydrochloride (300 mg) as a white amorphous solid. MS found: (M+H)+=344.32.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH2:13][Br:26])[CH2:3]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)CBr

Procedure:
3α-Hydroxy-16α-methyl-5α-pregnane-11,20-dione (5 g.) was dissolved in dry methanol (350 ml.) and treated at 0° with a solution of bromine (1 ml.) in dry methanol (24 ml.) at such a rate that the yellow colour disappeared before further addition. After completion of the addition the mixture was poured into water. The precipitated product was dried and dissolved in chloroform (20 ml.) and put onto a column of silica gel MFC (700 g.). Elution with benzene:ethyl acetate (21/2:1) gave the title compound (3.6 g.) as a foam, [α]D + 112.4°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.[CH2:15]([O:17][P:18]([O-:22])[O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)CC)C.C(Cl)Cl.CO>CO>[CH2:15]([O:17][P:18]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1)(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: Brc1ccnc(-c2cc(Br)ccn2)c1
Reactant: CCOP([O-])OCC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccnc(-c2cc(Br)ccn2)c1
Temperature: 98 °C
Reaction time: 0.17 h

Procedure:
2.0 g of 4,4'-dibromo-2,2-bipyridine (6.4 mmol), 0.9g of palladium tetrakistriphenylphosphine (0.8 mmol), 3.14 g of diethylphosphite (23 mmol) and 2.34 g of triethylamine (23 mmol) are measured into an argon filled 50 ml round bottom. flask, equipped with a cold finger (10 cm) and magnetic stirrer. This is heated on a 98° C. oil bath for 3 hours. The reaction is monitored with TLC on silica gel plates, DCM: MeOH (10:1), Rf-Lb=0.73. This is then cooled back to room temperature, and then the solidified mixture is added to 25 mls of methanol, stirred for 10 min. and evaporated to dryness under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[N:16]2[CH2:17][CH2:18][CH:19]([CH:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[CH2:20][CH2:21]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CC(C1CCN(c2c(S(C)(=O)=O)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1)N(C)C
Yield: 24.4 %

Procedure:
Following general procedure D, 1-{1-[6-bromo-3-(methylsulfonyl)quinolin-4-yl]piperidin-4-yl}-N,N-dimethylethanamine (35 mg, 0.079 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (9.4 mg, 24%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.23 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.24-8.13 (m, 2H), 7.74 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.4, 2.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.81-3.70 (m, 2H), 3.55 (s, 2H), 3.45 (s, 3H), 3.28-3.22 (m, 1H), 2.84 (s, 6H), 2.14 (d, J=7.9 Hz, 1H), 1.95 (d, J=11.0 Hz, 2H), 1.87-1.68 (m, 2H), 1.38 (d, J=6.7 Hz, 3H); ESI MS m/z 488 [C25H30ClN3O3S+H]+; HPLC>99% (AUC), tR=10.84 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[C:3]([C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:30]=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[CH:32]=[CH:33][CH:34]=2)([OH:4])[CH:2]([CH3:45])[CH3:1])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)c1c[nH]cn1
Yield: 85.9 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[4′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.55 g) and pyridine hydrochloride (831 mg), the title compound (1.31 g) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[F:1][C:2]([F:14])([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a mixture of 1.70 g of 4-(pentafluoroethyl)phenol, 6 ml of acetic acid and 2.0 ml of concentrated sulfuric acid, a mixture of 0.80 g of 69% nitric acid and 1 ml of acetic acid was added dropwise while ice-cooling, and stirred at room temperature for three hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.40 g of 4-(pentafluoroethyl)-2-nitrophenol.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=1)[C:40]#[N:41]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=3)[C:40]#[N:41])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#Cc1ccnc(Br)c1
Product: C[C@@H](c1ccc(-c2cc(C#N)ccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromoisonicotinonitrile following a procedure analogous to that described in Example 583. LC-MS Method 2 tR=1.419 min, m/z=478.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17 (s, 2H), 2.25 (m, 1H), 2.41-2.58 (m, 2H), 3.06 (m, 1H), 5.58 (m, 1H), 7.08 (d, 2H), 7.25-7.40 (m, 5H), 7.59 (d, 1H), 7.80 (d, 2H), 8.10 (s, 1H), 8.29 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:25]1([NH:28][C:22](=[O:24])[CH2:21][NH:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)NC1CC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of cyclopropylamine. Yield: 53 mg.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][OH:15])[CH2:5]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
A solution of 1.06 g (4.75 mmol) of 1-(prop-2-enyl)-(3-(R)-(hydroxymethyl))-4-(S)-(3-thienyl)pyrrolidine (from Step A) in 12.0 mL of CH2Cl2 at 0° C. was treated with 0.99 mL (5.7 mmol) of N,N-diisopropylethylamine and 855 mg (5.6 mmol) of t-butyldimethylsilyl chloride. After warming to rt and stirring for 20 h, the solution was partitioned between 100 mL of ether and 100 mL of H2O. After separating the phases, the aqueous layer was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 3:1 v/v hexanes/EtOAc to yield 1.24 g (77%) of the title compound: RF: 0.54 (3:2 v/v hexanes/EtOAc); 1HNMR (300 Mhz) δ 0.0 (s, 6H), 0.86 (s, 9H), 2.35 (m, 1H), 2.52-2.71 (m, 3H), 2.97-3.20 (m, 4H), 3.54-3.66 (m, 2H), 5.06-5.21 (m, 2H), 5.89 (m, 1H). 6.98-7.02 (m, 2H), 7.22 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[CH:5]=2.[ClH:13].O.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C>C(O)(C)C>[ClH:13].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1)=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[CH:5]=2
Reactant: O=C1CCNCC1
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(C3=CCNCC3)c(C)[nH]c2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2 g of 2-methyl-6-methoxy-1H-indole, 4 g of the hydrochloride of 4-piperidone monohydrate and 40 ml of acetic acid was stirred at 100° C. under an inert atmosphere for 90 minutes and the mixture was cooled and poured into a solution of 150 g of ice and 80 ml of 22° Be ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness and reduced pressure. The residue was empasted with hot ethyl acetate and the mixture was cooled and vacuum filtered. The product was washed with ethyl acetate and dried under reduced pressure to obtain 2.5 g of raw product which was dissolved in 50 ml of hot isopropanol. The solution was cooled and made acidic by dropwise addition of an isopropanol solution of gaseous hydrogen chloride. The mixture stood overnight after crystallization was induced and was vacuum filtered. The product was washed with isopropanol and was dried under reduced pressure to obtain 2.25 of 2-methyl-6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride melting at 270° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][C:24]=2[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32].Cl>C(O)(C)C>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][C:24]=4[C:23]=3[S:31]([NH2:34])(=[O:32])=[O:33])[CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: Nc1ccc2c(c1S(N)(=O)=O)CCC2
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)CCC4)n2)cc(OC)c1OC

Procedure:
(4-Chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (240 mg, 0.81 mmol) and 5-amino-indan-4-sulfonic acid amide (190 mg, 0.89 mmol) are suspended in isopropanol (15 ml). Conc. HCl (1.5 ml) is added. The mixture is heated to reflux for 1 h. The reaction mixture is separated between ethyl acetate (300 ml) and water (100 ml). NaHCO3 is added to achieve basic pH. The layers are separated. The organic layer is dried with Na2SO4 and evaporated. The residue is crystallized from ethyl acetate to give 5-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-indan-4-sulfonic acid amide.
Reaction SMILES: [I-].[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:76]/[O:77][CH3:78])/[C:28]([NH:30][CH:31]2[C:74](=[O:75])[N:33]3[C:34]([C:58]([O:60][CH:61]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:59])=[C:35]([CH2:38][P+:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(Cl)(Cl)Cl.CO>ClCCl>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:76]/[O:77][CH3:78])/[C:28]([NH:30][CH:31]2[C:74](=[O:75])[N:33]3[C:34]([C:58]([O:60][CH:61]([C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:59])=[C:35]([CH:38]=[P:39]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1)([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 93 %

Procedure:
A solution of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(triphenylphosphonio)methyl]-3-cephem-4-carboxylate iodide* (3.0 g, 2.5 m moles) in dichloromethane (40 ml) was shaken with 1N NaOH (10 ml) until the spot of the starting material disappeared on TLC (silica gel, CHCl3 --MeOH=10:1). Organic layer was separated and concentrated under reduced pressure. The residue was triturated with n-hexane and the product was collected by filtration to give 2.5 g (93%) of the title compound.