Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42]N(C)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42][N:32]([CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CN1CCN(CCN)CC1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN1CCN(CCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC1
Yield: 12 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2-(4-methyl-piperazine-1-yl)-ethyl amine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber glass (27 mg, 12% yield). 1H NMR (300 MHz, DMSO) δ: 7.63 (d, 1H, J=8.42), 7.52 (s, 1H), 7.25 (d, 1H, J=7.31), 4.59 (s, 2H), 4.24 (m, 10H), 4.11 (s, 2H), 3.58 (s, 2H), 2.98 (s, 3H), 2.78 (s, 3H). HRMS (M−H) calcd for C20H25N4Cl2O3: 439.1303. found: 439.1311.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:16]1([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:25][CH:24]([OH:26])[CH2:23][O:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: c1ccc(OCC2CO2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=S1(=O)CCN(c2ccc(OCC(O)COc3ccccc3)cc2)CC1
Yield: 58.3 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), phenylglycidyl ether (1.5 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.1 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.2 g (58%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].N1C=CC=CC=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([C:33]=2[S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]3[C:34]([C:33]=2[S:35]([NH:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:4]([OH:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:37])=[O:36])=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Reactant: COC(=O)C(O)[C@@H](N)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](O)[C@@H](NS(=O)(=O)c1c2ccccc2cc2ccccc12)c1ccccc1
Reaction time: 1.5 h

Procedure:
(3S)-3-Phenylisoserine methyl ester (I, 0.38 g, 1.95 mmol) is dissolved in methylene chloride (5 mL) and pyridine (1 mL) and the solution treated with a suspension of 9-anthracenesulfonylchloride (0.536 g, 1.95 mmol). The reaction is stirred at 23° for 90 min. The reaction is then poured into methylene chloride and extracted with hydrochloric acid (1 N) and aqueous bicarbonate (5%) and dried over magnesium sulfate. Concentration of the organic layer under reduced pressure produces crude product. This concentrate is chromatographed (silica gel 60; ethyl acetate/toluene, 20/80) to give the title compound, TLC (silica gel GF) Rf=0.38 in (ethyl acetate/toluene, 2/8); NMR(CDCl3, TMS) 3.11, 3.57, 4.18, 4.78, 6.22, 6.59, 6.67, 7.50, 7.55-7.75, 7.92, 8.09, 8.47 and 9.15 δ
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting powder was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 221.5 mg.
Reaction SMILES: [C:1](O)(=O)[C:2](O)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][NH2:19])[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1.C(C(CC)(CC)C([O-])([O-])[O-])C>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:1]([CH3:2])=[N:19][CH2:18][CH:16]3[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1
Reactant: NCC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=C(O)C(=O)O
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC#N
Product: CC1=NCC2C[N+]([O-])=C(c3ccccc3F)c3cc(Cl)ccc3N12
Reaction time: 1 h

Procedure:
A slurry of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide oxalate salt (VIII, EXAMPLE 6, 35 g, 85 mmol) and triethylorthoacetate (23.5 ml, 128 mmol) in acetonitrile (175 ml) is stirred at reflux for 2 hr during which time the 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide (VIII) dissolves and ethanol/acetonitrile (about 75 ml) is removed by distillation under ordinary pressure. TLC and HPLC analysis shows the reaction is complete. The temperature is adjusted to 40° and methyl t-butyl ether (175 ml) is added dropwise over about 1 hr. The resulting slurry is cooled to 5°, stirred 1 hr, the solids are collected and are washed with t-butyl ether. The product is dried in the vacuum oven at 35° to give the title compound as the oxalate salt, mp=178°-180°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].[OH-].[K+:17]>CO>[K+:17].[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:11](=[O:12])[C:10]([O-:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a mixture of 3-Bromobenzaldehyde (22.0 mL, 189.0 mmol) and pyruvic acid (15.8 mL, 227.0 mmol) in methanol (100.0 mL), was slowly added a solution of potassium hydroxide (19.0 g, 340.0 mmol) in methanol (100.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The resulting solid was washed with diethyl ether to give 47.0 g of the titled compound as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3](C1C=CC(NS(C2C=CC(C)=CC=2)(=O)=O)=CC=1)=[O:4].C([C:25]1[CH:41]=[CH:40][C:28]([NH:29][S:30]([C:33]2C=CC(C)=CC=2)(=[O:32])=[O:31])=[CH:27][CH:26]=1)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([C:27]1[CH:26]=[CH:25][CH:41]=[CH:40][C:28]=1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2)cc1
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccccc1C(=O)CBr

Procedure:
In a similar manner 4'-(2-bromoacetyl)-p-toluenesulfonanilide, (m.p. 174°-1765° with decomposition,) can be prepared by bromination of 4'-acetyl-p-toluenesulfonanilide (Preparation 1) [See R. H. Vloth, et al., J. Med. Chem. 9, 88 (1966)]. For this preparation anhydrous ether can also be used as solvent; benzoyl peroxide can be used as a catalyst. The product is crystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:56]1[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:56]2[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]2)=[O:33])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (200 mg), HOBt (1 eq.), EDAC (2 eq.), TEA (3 eq.) and (R)-pyrrolidin-3-ol (3 eq.) in DMF (4 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water (2×) and 10% sodium carbonate (2×). The DCM was dried, concentrated and purified on a silica gel column to give 21 mg of the titled compound. MS m/z 588 [M++1].
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CC[C@@H](O)C1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC[C@@H](O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (R)-1-(4-amino-butyl)-pyrrolidin-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ7.19 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.0, 10 Hz), 5.45 (s, 2H), 4.34 (m, 1H), 3.23 (m, 2H), 2.86 (dd, 1H, J=6.0, 10.4 Hz), 2.78 (m, 1H), 2.65-2.54 (m, 4H), 2.25 (s, 3H), 2.14 (m, 1H), 1.73 (m, 1H), 1.56 (m, 4H) ppm; MS (APCI, m/z): 484 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Fc1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: NC(=O)Cc1cc(Cl)nc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
2-(2-chloro-quinolin-4-yl)-acetamide (500 mg, 2.27 mmol) is dissolved in 1-methyl-2-pyrrolidinone (3.0 mL). N-methylpiperazin (1.3 mL, 5 eq.) is added and the reaction is stirred at 80° C. for 48 h. AcOEt (20 mL) is added and the precipitate is purified by FCC (AcOEVEtOH/28% NH4OH 80:18:1) to afford 2-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]-acetamide as a solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S, 4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S, 4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Product: COc1ccc(CN(Cc2ccc(OC)c([N+](=O)[O-])c2)c2ccc(F)cc2)cc1[N+](=O)[O-]
Yield: 91 %

Procedure:
4-Fluoroaniline and 4-methoxy-3-nitrobenzyl bromide were processed using the method described in Example 1A to provide 2.33 g (91%) of the title compound. MS (ESI; M+H) m/z=442.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2].C(ON=O)(C)(C)C.[ClH:31].CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:31])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 50 °C

Procedure:
steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:44]1([O:49][C:50](=[O:60])[C@H:51]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH2:52])[CH2:48][CH2:47][CH2:46][CH2:45]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:52][C@@H:51]([CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:50]([O:49][CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:60])=[CH:21][CH:22]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1ccc(OCCCN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1

Procedure:
From Intermediate 4B and L-phenylalanine cyclopentyl ester (Intermediate 16), LCMS purity 93%, m/z 598 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.50-2.10 (8H, m), 2.50 (2H, m), 3.35-3.40 (1H, m), 3.55-3.70 (2H, m), 4.40-4.50 (2H, m), 4.60 (1H, m), 5.40-5.45 (1H, m), 6.05-6.10 (1H, d), 7.40-7.65 (11H, m), 7.85 (2H, m). 7.90 (1H, m).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
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: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 100 °C
Yield: 76.6 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethylpyridazine (800 mg, 3.44 mmol) in 20 mL DMF is added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 4.1 mmol), followed with potassium carbonate (1.43 g, 10.3 mmol) and Pd(PPh3)4 (397 mg, 0.344 mmol) in a round bottom flask. The vial is evacuated and flushed with nitrogen. The reaction mixture is heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford the crude material. The mixture is purified by flash chromatography on silica gel, eluting with 3%-15% MeOH: DCM. Fractions containing the desired product are combined and concentrated to afford a brown solid (1.0 g, 77%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH3:47])[C:42]([O:48][CH3:49])=[CH:41][C:40]=1[F:50])=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1>CN(C=O)C>[CH2:46]([O:45][C:43]1[C:42]([O:48][CH3:49])=[CH:41][C:40]([F:50])=[C:39]([CH:25]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[N:37]=[C:36]([CH3:38])[O:35][N:34]=3)=[CH:31][CH:32]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)[CH:44]=1)[CH3:47]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c(F)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c(F)cc1OC
Temperature: 90 °C
Reaction time: 14 h
Yield: 63.1 %

Procedure:
After adding 16 mg of 2-hydrazinobenzoic acid hydrochloride and 25 μl of triethylamine to a solution of 85 mg of {2-(5-ethoxy-2-fluoro-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanyl-ethylidene}carbamic acid methyl ester (see Example (115b)) in 3 ml of DMF, the mixture was stirred at 90° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=2:1 mixed solvent. After adding 35 μl of acetic acid and 55 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 2-(3-{(5-ethoxy-2-fluoro-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)benzoic acid (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][C:23]=2[CH3:24])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[C:23]([CH3:24])=[CH:22][N:21]([CH2:30][O:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: COCBr
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Product: COCn1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, with the compound from Example 131, 3-(4-chlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and bromomethyl methyl ether.