Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Yield: 26.7 %

Procedure:
4-Amino-3-fluorobenzoic acid (500 mg, 3.22 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (888 mg, 3.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (926 mg, 4.83 mmol, EDCl) and triethylamine (984 mg, 898 μl, 6.44 mmol) were combined and stirred in acetonitrile (10 mL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane (30 mL) and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to give the title compound (355 mg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:34]([NH:33][C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[N:30][CH2:28][CH3:29])[CH3:35]
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: CCNC(=S)NCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN=C(NCC)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,N'-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N'-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:27][C@@:16]2([C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24]Cl)[C:18](=[O:26])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>>[CH2:1]([NH:5][C:6]([C@@H:8]1[CH2:27][C@@:16]2([C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][N:33]3[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]3)[C:18](=[O:26])[NH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=2)[O:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCN3CCC(O)CC3)C2=O)c2cc(F)ccc2O1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95.3 %

Procedure:
A mixture of (2S,4S)-N-butyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Reference Example 4, 17.0 g, 41.4 mmol), 4-hydroxypiperidine (8.36 g, 82.8 mmol), K2CO3 (7.43 g, 53.8 mmol) and N,N-dimethylformamide (68.0 ml, 880 mmol) was stirred for 5 hours at 80° C. After distilling off the solvent, the residue was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1), and evaporated in vacuo to dryness to give amorphous crystals of the desired compound (18.8 g, 95.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:16](O)=[O:17])[C:11](=[O:26])[CH:10]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:16]([NH:27][C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=2)=[O:17])[C:11](=[O:26])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
1.8 g (purity 76%, 3.2 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 734 mg (purity 92%, 35% of theory)
Reaction SMILES: ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[C:15]1=[O:22].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:13][N:14]1[CH2:18][CH2:17][N:16]([C:19]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)=[O:20])[C:15]1=[O:22]
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: CN1CCN(C(=O)Cl)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2ccc3c(c2)NC(=O)C3)C1=O
Reaction time: 5 h

Procedure:
bis(trichloromethyl)carbonate in tetrahydrofuran was added dropwise within 1 hour to the compound D78 in tetrahydrofuran in such a way that the internal temperature was kept at 55-60° C. The mixture was stirred for 5 h at this temperature. The formation of 3-methyl-2-oxoimidazolidine-1-carbonyl chloride was confirmed by TLC. The 6-aminoindolin-2-one (D4) was added to the mixture in situ and the mixture was refluxed for 4 h. The completion of reaction was monitored using TLC. The residue obtained after workup using saturated sodium carbonate was further purified using flash chromatography on silica gel to afford the title compound D79.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.[NH2:56][C@@H:57]([CH3:73])[CH2:58][N:59]1[CH:63]=[CH:62][C:61]([C:64]2[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=2)=[N:60]1>C(Cl)Cl>[C:1]([C:4]1[NH:5][N:6]=[C:7]([C:9]([NH:56][C@@H:57]([CH3:73])[CH2:58][N:59]2[CH:63]=[CH:62][C:61]([C:64]3[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=3)=[N:60]2)=[O:11])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (10.20 g, 66.2 mmol), DCM (195 ml) and DIPEA (11.52 ml, 66.2 mmol) were placed in to the reaction flask under nitrogen atmosphere. HBTU (3.27 g, 8.63 mmol), EDCI (12.68 g, 66.2 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (15 g, 57.5 mmol) were added in this order and the mixture was stirred overnight at RT. The solvent was distilled close to dryness under vacuum, 2-propanol (25 ml) was added and the mixture was distilled to dryness. 2-Propanol (127 ml) was added, heated to reflux, water (23 ml) was added and the mixture was stirred for 15 min. The mixture was cooled to RT, stirred overnight and cooled to 5° C. The precipitate was filtered, washed with 2×10 ml of cold 2-propanol:water (70:30) and dried under vacuum to obtain 18.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.17 (d, 3H), 2.50 (s, 3H), 4.21-4.53 (m, 3H), 6.93 (d, 1H), 7.31 (s, 1H), 7.81 (d, 1H), 7.86-8.07 (m, 3H), 8.40-8.54 (bs, 1H), 14.14 (bs., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:33]1([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:22]=[C:21]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)[CH:20]=[CH:19][C:3]=2[CH2:4][NH:5][C:6](=[O:18])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)Oc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A suspension of compound 1g (100 mg, 0.26 mmol), phenyl chloroformate (0.033 mL, 0.26 mmol) and potassium carbonate (72 mg, 0.52 mmol) in DCE (2 mL) was stirred at rt overnight. Additional phenyl chloroformate (0.015 mL, 0.13 mmol) was added and the reaction was stirred at rt for 24 h. The reaction was concentrated on a rotary evaporator and the residue purified by silica gel chromotagraphy (ethyl acetate) to afford compound 19a (157 mg, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:38]([S:56][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octadecanthiol.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[H-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[CH3:12][N:13]1[CH2:17][CH2:16][CH:15]([C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[C:14]1=[O:18]
Reactant: CCOC(=O)c1cccnc1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)c2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.8 %

Procedure:
Ethyl nicotinate (10.3 g, 66 mmol) and N-methyl-2-pyrrolidone (6.5 mL, 66 mmol) were dissolved in a dry toluene (200 mL) and sodium hydride (4 g) was added therein in batch. The mixture was stirred for 30 h under reflux, and then cooled to room temperature, and 5 mL methanol was added to quench the reaction. The reaction solution was poured into 1 mol/L of diluted hydrochloric acid (70 mL), extracted with dichloromethane. The extract was washed with saline and concentrated till dry to give 11.3 g colorless oily product (1-methyl-3-nicotinoyl-2-pyrrolidone) with a yield of 81%. 1HNMR (CD3OD, 300 MHz) δ: 9.21 (d, 1H), 8.75 (dd, 1H), 8.48 (dt, 1H), 7.60 (dd, 1H), 4.70 (d, 1H), 3.48-3.57 (m, 1H), 3.41-3.46 (m, 1H), 2.85 (s, 3H), 2.52-2.60 (m, 1H), 2.30-2.38 (m, 1H); ESI-MS 205.0 (M+H), 243.1 (M+K).
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[C:7]=1[Cl:1]
Reactant: Cl
Reactant: CC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(n1)C(=O)C(N)=C(Cl)C2=O

Procedure:
A slow stream of hydrogen chloride gas was passed through a solution of 7-acetamido-2-methylquinoline-5,8-dione (6, 230 mg, 1 mmol) in dry methanol (15 ml) at 60° C. for 48 h. (See Equation 11 below) The resulting acidic solution was neutralized with 2% sodium bicarbonate (10 ml), extracted with CH2Cl2 (5×30 ml) and dried over sodium sulfate (2.0 g, 20 min). Evaporation of the solvent in vacuo afforded 98 mg (42%) of pure (59) as red crystals: mp 270° C. (Dec., MeOH); 1H NMR (CDCl3) δ 8.31 (1H, d, J=8.0 Hz, H-4), 7.47 (1H, d, J=8.0 Hz, H-3), 5.70 (2H, brs, NH2), 2.68 (3H, s, CH3); IR (KBr) vmax 3471, 3329, 3191, 3085, 2960, 2924, 1649, 1605, 1587, 1573, 1382, 1370, 1326, 1273, 1259, 1164, 737 cm−1; EIMS, m/e (relative intensity) 223 (M+1, 100), 189 (4.1), 133 (0.4), 81 (0.8), 69 (1.2); EIMS, m/e (relative intensity) 224 (M+2, 27.3), 222 (M+, 97.2), 195 (7.4), 187 (M-CI, 100), 166 (5.3), 131 (10.4), 104 (12.1), 77 (14.9), 64 (10.5); HRMS, m/e for C10H7ClN2O2 calcd 222.0196, found 222.0194.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[CH2:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNS(=O)(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: O
Product: CC(C)CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 150 °C
Yield: 89.5 %

Procedure:
A microwave vial was charged with 4-fluoro-N-isobutyl-benzenesulfonamide (1.0 g, 4.32 mmol), piperazine (1.86 g, 21.60 mmol) and water (20 mL) and heated at 150° C. for 1 hour using a microwave reactor. The solid from the reaction mixture was collected by filtration, washed with water and dried to give N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.15 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.33 (t, J=6.5 Hz, 1H), 3.32-3.25 (m, 4H), 3.05-2.99 (m, 4H), 2.73 (t, J=6.6 Hz, 2H), 1.78-1.65 (m, 1H), 0.87 (d, J=6.7 Hz, 7H). LCMS (m/z, Method A) ES+ 298.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cc2O1

Procedure:
In accordance with the above preferred reaction scheme 2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone 2 are reacted with sodium cyanoborohydride in methanol, giving 3-chloro-alpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 3which is reacted with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by separation of isomers, giving cyclized derivative 4 which is reacted with boron tribromide in dichloromethane, giving (R*, R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1, 3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 6 which is then reacted first with sodium hydroxide in ethanol and then with hydrogen chloride gas in methanol, giving the product (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl) 2-hydroxyethyl)-amino)propyl)-2,3-benzodioxole-2,2-dicarboxylic acid, dimethyl ester 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(c3cccc(OC)c3)Oc3ccc(C(=O)O)cc3O2)c1
Reactant: C1CCNCC1
Product: COc1cccc(C2(c3cccc(OC)c3)Oc3ccc(C(=O)N4CCCCC4)cc3O2)c1

Procedure:
This compound was prepared from 2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; waxy solid, MS: m/e=446 ([M+H]+].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:21][CH2:22][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:28][CH2:29]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (359 mg, 2.06 mmol) in ethanol (4 mL), triethylamine (286 μL, 2.06 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1-one (Reference Example 16) (563.7 mg, 1.87 mmol) in ethanol (5.4 mL) was added dropwise, and the obtained solution was stirred at room temperature for 22 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (177 mg, 0.42 mmol, 22%) as an amorphous product.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[CH2:10]([NH:17][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[OH:1])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1sccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1sccc1O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
1.44 g of 3-hydroxy-thiophene-2-carboxylic acid were dissolved in 100 ml of dichloromethane, and 2.18 ml of benzylamine and 5.00 ml of a 50% strength 1-propanephosphoric anhydride solution in acetic acid were added. The reaction mixture was stirred at 22° C. for 2 h and, after addition of 100 ml of saturated sodium bicarbonate solution, extracted twice with 100 ml of dichloromethane each time. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product with the molecular weight of 233.3 (C12H11NO2S), MS (ESI): 234 (M+h+) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[CH:17][CH:18]=3)[N:11]=[C:10]([C:21]([N:57]3[CH2:61][C:60](=[O:62])[NH:59][CH2:58]3)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 110A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. In order to remove the 1,1′,1″-phosphoryltripyrrolidine the product is taken up in a little tetrahydrofuran, water is added to the mixture until a precipitate forms, the tetrahydrofuran is removed in vacuo, and the precipitate is collected by suction filtration and dried under high vacuum. 42 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1)#[N:18]
Reactant: COC(=O)N1CCc2ccc(Br)cc2C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COC(=O)N1CCc2ccc(C#N)cc2C1
Yield: 82.9 %

Procedure:
A mixture of 7-bromo-2-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (12.0 g, 0.044 mol), copper (I) cyanide (8.7 g, 0.097 mol) and N-methyl-2-pyrrolidinone (100 ml) was heated at reflux for 4 h, cooled, then partitioned between dilute aqueous ammonia (500 ml) and ethyl acetate (300 ml). Organic phase was washed with dilute aqueous ammonia (100 ml), water (4×100 ml), then dried (Na2SO4) and evaporated in vacuo to give the title compound as an oil (7.89 g, 83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH:18]=[CH2:19]>CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:19]([O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)[CH:18]=[CH2:17]
Reactant: C=CCI
Reactant: Oc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 1H-indazol-6-ol (20.0 g, 150 mmol) in acetone (450 mL) was added pulverized potassium carbonate (22.4 g, 162 mmol), cesium carbonate (2.00 g, 5.7 mmol), and allyl iodide (14.63 mL, 160 mmol) and the mixture was stirred for 18 h at ambient temperature. Additional potassium carbonate (5.00 g, 36 mmol) and allyl iodide (1.4 mL, 15 mmol) were added and the mixture was stirred for 2 h followed filtration. Water (200 mL) was added to the filtrate and the volume of the mixture was reduced by about half in vacuo and extracted with dichloromethane (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to give a yellow solid (14.7 g, 56%): mp 110-112° C.; LC/MS (+APCI) m/z 175 (M+H). Unreacted starting material was recovered (4.71 g).