Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][N:5]([C:7]([NH:21][CH2:22][CH3:23])=[N:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)(=[O:11])=[O:10])[N:4]=[CH:3]1.C(O)(=O)C>CCO.O.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([S:9]([N:8]=[C:7]([N:5]2[CH2:6][C:2]([CH3:1])([CH3:24])[CH:3]=[N:4]2)[NH:21][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CCNC(=NS(=O)(=O)c1cccc([N+](=O)[O-])c1)N1CC(C)(C)C=N1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCNC(=NS(=O)(=O)c1cccc(N)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
In a mixture of 50 mL EtOH and 25 mL water, 1.11 g N-[(4,4-Dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-3-nitro-benzenesulfonamide was dissolved. Subsequently, 1.05 g iron and 1.08 mL acetic acid were added, and the mixture was refluxed for 4 h. After cooling to room temperature, the mixture was filtered over Hyflo and the Hyflo was rinsed with MeOH. The alcohols were evaporated from the filtrate, and 5% aqueous NaHCO3 and DCM were added. The material insoluble in these phases was filtered off, the organic phase was separated and the aqueous phase extracted once more with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 1.02 g (100%) of 3-amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as a brown foam. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.19 (s, 6H), 3.42-3.51 (m, 2H), 3.73 (s, 2H), 3.93 (br.s., 2H), 6.71-6.79 (m, 2H), 6.90 (br.s., 1H), 7.20 (t, J=7.83 Hz, 1H), 7.24-7.31 (m, 2H).
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[NH2:39][C:40]1[N:44](C(OC(C)(C)C)=O)[N:43]=[C:42]([C:52]2[CH:98]=[CH:97][C:55]([O:56][CH2:57][C:58]3[S:62][C:61]([N:63]4[CH2:72][CH2:71][C:70]5[C:65](=[C:66]([C:73](=[O:92])/[N:74]=[C:75]6/[S:76][C:77]7[CH:91]=[CH:90][CH:89]=[CH:88][C:78]=7[N:79]/6COCC[Si](C)(C)C)[CH:67]=[CH:68][CH:69]=5)[CH2:64]4)=[N:60][C:59]=3[C:93]([O:95]C)=[O:94])=[CH:54][CH:53]=2)[C:41]=1[C:99]#[N:100]>>[NH2:39][C:40]1[NH:44][N:43]=[C:42]([C:52]2[CH:53]=[CH:54][C:55]([O:56][CH2:57][C:58]3[S:62][C:61]([N:63]4[CH2:72][CH2:71][C:70]5[C:65](=[C:66]([C:73](=[O:92])[NH:74][C:75]6[S:76][C:77]7[CH:91]=[CH:90][CH:89]=[CH:88][C:78]=7[N:79]=6)[CH:67]=[CH:68][CH:69]=5)[CH2:64]4)=[N:60][C:59]=3[C:93]([OH:95])=[O:94])=[CH:97][CH:98]=2)[C:41]=1[C:99]#[N:100]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1COc1ccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)cc1
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1c(-c2ccc(OCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)n[nH]c1N

Procedure:
The title compound 45 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 45E: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.67 Hz, 1H), 7.78 (d, J=7.98 Hz, 1H), 7.59-7.71 (m, 3H), 7.33-7.48 (m, 4H), 7.05 (d, J=7.59 Hz, 1H), 6.83 (d, J=7.67 Hz, 1H), 5.54 (s, 2H), 4.77-4.86 (m, 4H), 3.74 (t, J=5.68 Hz, 2H), 3.04 (t, J=5.83 Hz, 2H). MS (ESI(+)): m/z 647 (M−H).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[Cl-].[C:31]([CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:32].O>ClCCl>[C:31]([CH:33]=[CH:3][C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)#[N:32]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=CC#N)cc3ccccc13)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of a 50% strength sodium hydroxide solution is added to a solution of 0.36 g (1 mmol) of the compound of Example 1 and of 0.34 g (1 mmol) of cyanomethyltriphenylphosphonium chloride in 3 ml of dichloromethane. The mixture is stirred at ambient temperature for 1 hour. 10 ml of water are then added and the aqueous phase is extracted with twice 10 ml of dichloromethane. The organic phase is washed, dried and evaporated. A purification is performed on a silica column (CH2Cl2 eluent).
Reaction SMILES: FC(F)(F)C([O-])=O.FC1C=CC(CC2N3C=C(C)C=C3C(=O)NC=2)=CC=1C(N1CCC[NH2+]CC1)=O.[F:36][C:37]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]2[N:52]3[CH:53]=[C:54]([CH3:56])[CH:55]=[C:51]3[C:50](=[O:57])[NH:49][CH:48]=2)=[CH:42][C:38]=1[C:39]([OH:41])=[O:40].[Cl:58]N1C(=O)CCC1=O>C1COCC1>[Cl:58][C:53]1[N:52]2[C:47]([CH2:46][C:43]3[CH:44]=[CH:45][C:37]([F:36])=[C:38]([CH:42]=3)[C:39]([OH:41])=[O:40])=[CH:48][NH:49][C:50](=[O:57])[C:51]2=[CH:55][C:54]=1[CH3:56]
Reactant: Cc1cc2c(=O)[nH]cc(Cc3ccc(F)c(C(=O)O)c3)n2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1cc2c(=O)[nH]cc(Cc3ccc(F)c(C(=O)N4CCC[NH2+]CC4)c3)n2c1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]cc(Cc3ccc(F)c(C(=O)O)c3)n2c1Cl

Procedure:
A mixture of Example 4, D6 (1 eq) and N-chlorosuccinimide (2 eq) in THF was stirred at RT. The solvent was removed under reduced pressure and the resulting crude was used as such in the next step without purification. MS (ES) C16H12ClFN2O3 requires: 334, found: 335 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(CC#C[Si](C)(C)C)[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(F)cc1)C2

Procedure:
Desilylation and hydrolysis of ethyl [6,7-dichloro-1-oxo-2-(p-fluorophenyl)-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate with sodium hydroxide in ethanol according to the procedure of Example 1, STEP (c), affords the title compound, m.p. 189°-190°.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:40]4[C:39](=[CH:38][CH:37]=[C:36]([O:35][C:34]([F:45])([F:44])[F:33])[CH:41]=4)[NH:42][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 578.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:34])([CH3:33])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:5]=2>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:3]([CH3:34])([CH3:33])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(NCCN3CCOCC3)ccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(NCCN3CCOCC3)cc21

Procedure:
Tert-butyl 2-(2-hydroxy-1,1-dimethyl-7-(2-morpholinoethylamino)-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (25 mg, 53 μmol) was dissolved in TFA (2 mL) at room temperature for 30 minutes and concentrated to give crude product. The crude product was purified via preparatory TLC to give the title compound. MS (ESI) m/z: Calculated; 417.5: Observed; 418.1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With cooling with ice, 110 ml of fuming nitric acid was gradually added to 27.7 g of methyl 2-fluoro-4-[(2-pyridinylcarbonyl)amino]benzoate, and stirred at room temperature for 1.5 hours. With cooling with ice, the reaction liquid was gradually added to a solution of sodium carbonate (138 g) in water (2000 ml), and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 27.5 g of the entitled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([F:36])([F:35])[F:24])[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccccc2C(F)(F)F)c1
Yield: 60.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 2-(trifluoromethyl)phenylboronic acid (0.033 g; 0.173 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.346 mmol), sodium iodide (0.052 g; 0.346 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (61%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=O)[CH:24]=[CH:23][C:21]=3[N:22]=2)=[C:14]([F:35])[CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[O:8]1[CH2:9][CH2:10][CH2:11][O:6][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH2:1])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[C:14]([F:35])[CH:13]=1
Reactant: [Li]CCCC
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 1.80 mL, 4.50 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.78 g, 5.00 mmol) in THF (10 mL) at −78° C. and the mixture was warmed to 0° C. over 30 min. The suspension (1 mL, about 3 equiv Wittig reagent) was added to a suspension of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-benzo[d]thiazol-6-yl)(pyridine-2-yl)methanone (0.09 g, 0.21 mmol) in THF (1 mL) and the mixture was stirred for 16 h at RT. The solvent was remove under vacuum and the resulting oil was purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridin-2-yl)vinyl)benzo[d]thiazole as a white solid. MS (ESI) m/z: Calculated: 418.1; Observed: 419.1 (M++1).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[OH-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 84.7 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.109 g, 4.295 mmol) in t-butyl methyl ether (17 ml), sodium hydroxide (0.164 g, 4.10 mmol) was added and the mixture was stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.955 g, 2.40 mmol) in t-butyl methyl ether (3 ml), and water (0.32 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water (5.6 ml) was added to the solution and stirred, and then, let to stand and separated into two layers. The aqueous layer was extracted twice with ethyl acetate (4 ml). The organic layers were combined, sequentially washed with 3% aqueous sodium chloride (6 ml) and saturated aqueous sodium chloride (6 ml), and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 33 g; ethyl acetate:hexane=1:4) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (1.079 g; 2.033 mmol; yield: 84.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3OCC#N)n1)CCOC(=O)N2C
Yield: 50 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a white solid (55 mg, 50%). mp: 245-247° C., MS (ESI+): 481 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.40 (d, J=8 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.17-7.07 (dt, 3H), 6.71 (s, 1H), 4.92 (s, 1H), 4.48 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.41 (s, 3H), 2.85 (t, J=6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Br)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CNC.O.[C:35](OCC)(=O)[CH3:36]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:36][CH2:35][CH2:26][C:25]5=[O:28])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: CCOC(C)=O
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoacetamidomethylindole (170 mg) obtained in Example 374, a 2 M solution (2.2 ml) of dimethylamine in tetrahydrofuran and dimethylformamide (5 ml) was stirred at room temperature for 2 hr. Then water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by Chromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (35 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][O:8][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.[N:49]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([N:52]3[CH2:51][CH2:50][N:49]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][CH2:53]3)=[O:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1noc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2noc3cc(Br)ccc23)CC1
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A suspension of (6-bromo-1,2-benzisoxazol-3-yl)acetic acid (Intermediate 32) (0.06 g) and HATU (0.09 g) in dry tetrahydrofuran (2 ml) was stirred at room temp. for 5 min. 1-Hydroxybenzotriazole (0.03 g) and 1,1-dimethylethyl 1-piperazinecarboxylate (0.04 g) were added and the reaction mixture was stirred for a further 18 h. The solvent was removed under vacuum and the residue was partitioned between dichloromethane and 2N aqueous sodium carbonate. The layers were separated and the organic layer was applied to a Varian Bond-Elut SPE cartridge (silica, 5 g ) eluting sequentially with dichloromethane, chloroform, ether and ethyl acetate to give the title compound as a white solid (0.09 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1C(=O)N([Cl:31])C(=O)C1>>[Cl:31][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=2[CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[NH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Product: Cc1cc(C)c2[nH]cc(Cl)c2c1Cc1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized by a chlorination of 2-((5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile using NCS analogously to the preparation of Example 85. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (s, 1H) 11.29 (br. s., 1H) 7.98 (d, J=0.76 Hz, 1H) 7.75-7.87 (m, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.44-7.55 (m) 7.39-7.44 (m) 6.86 (s, 1H) 4.75 (d, J=4.55 Hz, 2H) 2.42 (s, 3H) 2.24 (s, 3H). HRMS calcd. for C13H16ClN4 (M+H)+ 335.1058. found 335.1062.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:25])[C:16]2([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18][O:17]2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:26]([O:25][CH:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:16]1([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18][O:17]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1(C(O)c2ccnc(OCc3ccccc3)c2)CCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(C(OC(C)=O)c2ccnc(OCc3ccccc3)c2)CCCO1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4.23 g of methyl 2-[[2-(benzyloxy)-4-pyridyl](hydroxy)methyl]tetrahydro-2-furancarboxylate in 20 ml of dichloromethane were added 5 ml of acetic anhydride, 5 ml of pyridine and 0.43 g of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate and 100 ml of hydrochloric acid (2N) were added thereto. The organic layer was sequentially washed with 100 ml of water, 100 ml of saturated aqueous sodium hydrogencarbonate and 100 ml of brine, dried over magnesium sulfate and evaporated, to give 4.52 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][N:11]([CH:17]([CH3:21])[C:18]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: CCOc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
89 mg (purity 86%, 0.22 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 47 mg (0.24 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 32 mg (purity 89%, 25% of theory)
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[S:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2].CC[O-].[Na+]>C1COCC1.CCO>[CH3:18][C:13]1([CH3:19])[C:12]2[CH:20]=[C:8]([C:5]3[NH:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=3)[CH:9]=[CH:10][C:11]=2[NH:16][C:15](=[S:17])[O:14]1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)OC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Temperature: 80 °C
Yield: 73.3 %

Procedure:
To a solution of tert-butyl 2-cyano-5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (0.5 g, 1.3 mmol, 1 eq) in THF (5 mL) was added NaOEt (0.27 g, 3.9 mmol, 3 eq) in EtOH (5 mL) and the reaction was heated to 80° C. for 2 h. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the title compound (0.27 g, 73%) as a brown powder, mp 261–262° C. 1H NMR (DMSO-d6) δ 1.68 (s, 6 H), 6.72–6.73 (m, 1 H), 6.99–7.01 (m, 1 H), 7.06 (d, 1 H, J=7.9 Hz), 7.66–7.70 (m, 2 H), 12.26 (s, 1 H), 12.62 (s, 1 H); MS (ESI) [M−H]−=282; Anal. Calcd. For C15H13N3OS: C, 63.58; H, 4.62; N, 14.83. Found: C, 63.25; H, 4.78; N, 15.11.