Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH:27][C:37](=[O:38])[CH2:36][Br:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 66.58 mmol, 1.0 equiv; example 1/step 4) in dichloromethane (250 mL) at 0° C. were slowly added triethylamine (16.84 g, 166.46 mol, 2.5 equiv) and bromoacetyl chloride (20.96 g, 133.17 mol, 2.0 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 2 h at rt. The reaction mixture was cooled again to 0° C., diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over Na2SO4, concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with hexane/ethyl acetate (65:35) to obtain 23.1 g (70%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.40 (s, 9H), 2.92 (br s, 2H), 3.62 (hr s, 1H), 4.03 (d, J=7.1, 2H), 4.30 (s, 2H), 4.72 (d, J=5.1, 2H), 5.24 (dd, J=10.5 Hz, J=1.0, 1H), 5.35 (dd, J=16.6 H, J=0.7, 1H), 5.50 (d, J=7.7 Hz, 1H), 5.98-6.05 (m, 1H), 6.82(d, J=8.8 Hz, 1H), 7.68 (dd, J=8.6 Hz, J=1.5 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H), 9.43 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cc(F)ccc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c4) the title compound is obtained as off-white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:9]([C:11]2[CH:12]=[N:13][C:14]([C:20]3[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:28][CH3:29])=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])[OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.I[CH2:31][CH3:32].O>CN(C=O)C>[CH:3]1([CH:9]([O:10][CH2:31][CH3:32])[C:11]2[C:16]([O:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]3[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:28][CH3:29])=[N:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(OCC)C1CCCCC1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.3 mmol) is added to a solution of cyclohexyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol (74 mg, 0.2 mmol) in DMF (0.5 mL) at room temperature. The resulting mixture is stirred for 30 minutes. Iodoethane (31 mg, 0.2 mmol) is then added and the mixture is stirred for an additional 1 hour. Water (1 mL) is added to the above mixture and the aqueous layer is extracted with ethyl acetate (2×2 mL). The combined organic layers are dried and concentrated in vacuo. The crude product is purified with PTLC (hexanes/ethyl acetate 6:1) to give 5-(cyclohexyl-ethoxy-methyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine. 1H NMR: (CDCl3) 8.50 (s, 1H), 7.28 (t, 1H), 7.12 (d, 2H), 6.70 (S, 1H), 4.45 (d, 1H), 4.03 (q, 2H), 3.34 (m, 2H), 2.34 (m, 4H), 2.02 (br, 1H), 1.73 (m, 4H), 1.21 (m, 4H), 1.05 (m, 13H).
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([CH2:2][CH3:3])([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CCBr
Reactant: CCN(CC)CCCOc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCCOc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1
Temperature: -30 °C

Procedure:
To a Grignard reactant prepared from 7.2 g. of magnesium turnings and 32.6 g. of ethyl bromide in 120 ml. of dry ether a solution of 25.6 g. of 4-chloro-4'-[3-(diethylamino)-propoxy]-benzophenone in 300 ml. of dry ether is added dropwise, with stirring at -30° C. The reaction mixture is refluxed for 30 minutes. After cooling, it is poured onto a solution of ammonium chloride in ice water. The aqueous phase is extracted with ether, the ethereal phase is washed to neutral with water, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. Distillation of the residue in vacuo yields 15.3 g. of the title compound, boiling at 212° to 214° C./13.3 Pa.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[C:13](O)([C:15]([F:18])([F:17])[F:16])=O>>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(Br)c2nc(C(F)(F)F)[nH]c2c1
Temperature: 85 °C
Yield: 53.1 %

Procedure:
In a 250 mL round-bottom flask a mixture of 3-bromo-5-nitrobenzene-1,2-diamine (10 g, 43.1 mmol) and TFA (23.24 mL, 302 mmol) was heated to 85° C. for 17 hours. The mixture was allowed to cool to RT, and then was concentrated in vacuo to remove the excess TFA. The residue was partitioned between water (100 mL) and ether (100 mL; not soluble in dichloromethane). The phases were separated, and the organic layer was dried over Na2SO4, then filtered and concentrated in vacuo to provide 4-bromo-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (7.1 g, 22.90 mmol, 53.1% yield) as a brown solid. LCMS and NMR are consistent with structure (NMR contains a trace of ether). MS (ES+) m/e: 308.9, 310.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 15.09 (br. s., 1H) 8.49-8.66 (m, 1H) 8.36-8.48 (m, 1H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].CC(C)([O-])C.[K+]>C1COCC1>[CH3:16][O:15][C:11](=[O:14])[CH2:12][O:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc([N+](=O)[O-])cn1
Yield: 17.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol) and methyl glycolate (0.67 mL, 8.2 mmol) in THF (10 mL) was added potassium tert-butoxide (0.92 g, 8.2 mmol) in one portion. After 1 h the reaction was poured onto ice, the solids isolated by filtration and washed with water. Purification on silica gel by column chromatography using 20% ethyl acetate in hexanes gave 0.23 g (18%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.02 (m, 1H), 7.15 (m, 1H), 5.06 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH:20]=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>FC(F)(F)C(O)=O.ClCCl.CC(C)=O>[C:1]1([N:7]2[C:11]([S:12][CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:29][CH2:30][C:31]([OH:33])=[O:32])[CH:20]=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOc1ccc(OCC(=O)O)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Temperature: 0 °C
Yield: 17 %

Procedure:
A solution of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (Example 52, 0.47 g) in trifluoroacetic acid (5-10 mL) and dichloromethane (5-10 mL) was stirred at room temperature for two hours, then stripped of volatiles, then stripped three times more from dichloromethane, then stripped once more from acetone. A solution of the residual oil in acetone (1 mL) was added to ice-water (100 mL) containing concentrated hydrochloric acid (1 mL). The resulting solid was collected, washed with water and dried (0.34 g). A solution thereof in dichloromethane was eluted through silica gel in a 15-mL sintered glass funnel with chloroform-methanol (95:5) affording 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-carboxymethoxysaccharin, 70 mg, 17% yield, mp 187°-189° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[PH2:24])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([Li])[CH2:42][CH2:43][CH3:44].S([O-])(=O)(=O)C>CCCCCC.C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:24]2[C:44]3[C:43](=[CH:2][CH:1]=[CH:5][CH:10]=3)[CH2:42][CH:41]2[CH:7]([CH3:8])[CH3:6])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P)cc1C(C)(C)C
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P2c3ccccc3CC2C(C)C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Under a nitrogen atmosphere, 1.0 g (1.72 mmol) of 2-(bis(3,5-di(tert-butyl)-4-methoxyphenyl)phosphino)phenylphosphine was added to 30 ml of THF, followed by cooling with an ice bath. Then, a 1.6M solution of 1.1 ml (1.72 mmol) of n-butyllithium in hexane was added dropwise thereto and, after dropping, the mixture was stirred for 1 hr, a solution of 448 mg (1.72 mmol) of MESYLATE in 10 ml of THF was added dropwise thereto, stirred for 1 hr and, after removing the ice bath, the mixture was stirred for 1 hr at room temperature. Following recooling with an ice bath, a 1.6M solution of 1.6 ml (2.58 mmol) of n-butyllithium in hexane was added dropwise thereto, after dropping, the ice bath was removed and the mixture was stirred overnight at room temperature. 1 ml of water was added to the reaction mixture to quench the reaction and the solvent was distilled off. 10 ml of water was added to the residue and extracted 3 times each with 20 ml of Et2O, and the combined organic layer was washed with 10 ml of water, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 337 mg of the title compound. (Yield: 27%)
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH2:83][CH2:82][C:81]2=[O:86])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:88].[Na+].[Na+].[Na+].[Na+].[CH3:93][C:94]1([CH3:161])[C:102]2[C:97](=[CH:98][CH:99]=[C:100]([S:103]([O-:106])(=[O:105])=[O:104])[CH:101]=2)[N:96]([CH2:107][CH2:108][CH2:109][S:110]([O-:113])(=[O:112])=[O:111])/[C:95]/1=[CH:114]/[CH:115]=[C:116](\[C:141]1[CH:146]=[CH:145][CH:144]=[C:143]([CH2:147][CH2:148][CH2:149][CH2:150][C:151](ON2C(=O)CCC2=O)=[O:152])[CH:142]=1)/[CH:117]=[CH:118]/[C:119]1[C:127]([CH3:129])([CH3:128])[C:126]2[C:121](=[CH:122][CH:123]=[C:124]([S:130]([O-:133])(=[O:132])=[O:131])[CH:125]=2)[N+:120]=1[CH2:134][CH2:135][CH2:136][S:137]([O-:140])(=[O:139])=[O:138].[Na+].[Na+].[Na+]>>[CH3:93][C:94]1([CH3:161])[C:102]2[C:97](=[CH:98][CH:99]=[C:100]([S:103]([O-:106])(=[O:105])=[O:104])[CH:101]=2)[N:96]([CH2:107][CH2:108][CH2:109][S:110]([O-:113])(=[O:112])=[O:111])/[C:95]/1=[CH:114]/[CH:115]=[C:116](\[C:141]1[CH:146]=[CH:145][CH:144]=[C:143]([CH2:147][CH2:148][CH2:149][CH2:150][C:151]([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH:83]=[CH:82][C:81]2=[O:86])=[O:152])[CH:142]=1)/[CH:117]=[CH:118]/[C:119]1[C:127]([CH3:129])([CH3:128])[C:126]2[C:121](=[CH:122][CH:123]=[C:124]([S:130]([O-:133])(=[O:132])=[O:131])[CH:125]=2)[N+:120]=1[CH2:134][CH2:135][CH2:136][S:137]([O-:140])(=[O:139])=[O:138].[Na+:88].[Na+:88].[Na+:88]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)C=CC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 23 is prepared analogously to compound 21 (Example 27), except that compound 15 is used as a starting material.
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(C)CC(=O)C>[CH2:1]1[C@@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)COCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@H]21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
32.48 g of (S)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in Preparation 3), 22.7 g of ethyl 2-chloroethoxyacetate, 48.9 g of sodium carbonate and 0.79 g of sodium iodide were added to 340 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, it was cooled to room temperature and was filtered using a Celite filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and hexane, to give 44.85 g (yield 91%) of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][CH:14]=3)=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:23]1[C:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:27]([CH3:37])[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:28]2[C:23]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([C:13]5[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][CH:14]=5)[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)=[N:24][CH:25]=[N:26][C:27]=2[CH3:37])=[CH:35][CH:34]=1
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)s1
Temperature: 120 °C
Yield: 46.9 %

Procedure:
A mixture of N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (220 mg, 0.68 mmol), 4-chloro-5-[(4-fluorophenyl)methyl]-6-methylpyrimidine (reagent preparation 5) (152 mg, 0.64 mmol) and diisopropylethylamine (500 mg, 3.87 mmol) in N-methylpyrrolidine (4 mL) was heated in a microwave reactor at 120° C. for 3 h. The reaction mixture was concentrated, diluted with water (10 mL), the precipitate was filtered off, washed with water (2×5 mL) and methanol (5 mL), and dried to provide N-[5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidine-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide (147 mg, 47% yield) as a off-white solid. MS (EI) C26H24FN5O2S: 490 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]1([OH:13])[CH2:12][O:11][CH2:10]1.[C:14]([Zn]C#N)#[N:15]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:3]([C:9]2([OH:13])[CH2:12][O:11][CH2:10]2)=[CH:4][N:5]=[C:6]([C:14]#[N:15])[CH:7]=1
Reactant: N#C[Zn]C#N
Reactant: OC1(c2cnc(Cl)cc2Cl)COC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C2(O)COC2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 155.7 %

Procedure:
To a solution of 3-(4,6-dichloropyridin-3-yl)oxetan-3-ol (example 123a, 5.0 g, 22.7 mmol) in dry DMF (100 ml) under argon atmosphere was added dicyanozinc (1.47 g, 12.5 mmol), DPPF (1.26 g, 2.27 mmol) and Pd2(dba)3 (1.04 g, 1.14 mmol). The reaction mixture was then stirred at 100° C. for two hours. DMF was removed in vacuo and the obtained residue was dissolved in ethyl acetate and poured into a separatory funnel. The organic phase was extracted with a saturated solution of ammonium chloride (colloids formed and were removed by filtration on a pad of celite). The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (4.1 gr, 86%); MS (ESI, m/z): 211.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O.O.[Sn](Cl)Cl.[OH-].[Na+]>CO.Cl>[Cl:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cccc(Cl)c1N
Reaction time: 3 h
Yield: 101.7 %

Procedure:
12.5 g (72.4 mmol) of 3-chloro-2-nitroaniline was dissolved in methanol (250 ml), and a solution prepared by dissolving 57.2 g (253 mmol) of tin (II) chloride dihydrate in concentrated hydrochloric acid (75 mL) was added dropwise. The reaction mixture was heated with stirring for 3 hours, and concentrated under reduced pressure. Water was added to the residue thus obtained, and the solution was alkalinized with a 25% aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extracted organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to obtain 10.5 g (yield: >99%) of 3-chloro-1,2-phenylenediamine as a pale magenta-colored liquid.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[CH2:10]([SH:13])[CH2:11][SH:12].C(N(CC)CC)C>CN(C=O)C>[SH:12][CH2:11][CH2:10][S:13][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CCl)COC(=O)N1
Reactant: SCCS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(CSCCS)COC(=O)N1
Temperature: 90 °C

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.85 g, 12.4 mmol) in DMF (5 ml) was added 1,2-ethanedithiol (10.0 ml, 119 mmol). Triethylamine (2.0 ml, 14 mmol) was added, and the solution heated to 90° C. for 2 h, then cooled to RT and concentrated in vacuo. Purification of the residue by flash chromatography (30%→80% EtOAc in hexanes) afforded a mixture of the title compound and various EDT disulfide adducts which was used without further purification. ESI/APCI expected for C7H13NO2S2: 207.04. Found: 208 (MH+), 300 (MH++EDT), 414 (MNa++2 EDT).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:30])[NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>O>[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)CCCBr
Reactant: CC(C)(C)OC(=O)NCC1CCCc2c(Oc3ccc(C#N)cn3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and heat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester as a colorless glass.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc([N+](=O)[O-])cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cn1

Procedure:
A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine (2 M in THF, 15 mL, 30 mmol) in methylene chloride (40 mL) was heated at 50 degrees overnight. After cooling to room temperature, the reaction mixture was concentrated to give methyl-(5-nitro-pyridin-2-yl)-amine that was used in the following step without purification. Acetic anhydride (9.3 mL, 98.5 mmol) was added to the solution of methyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24 mL, 197 mmol), and a catalytic amount of 4-dimethylamino-pyridine (DMAP) in methylene chloride (40 mL). The resulted mixture was heated at 90 degrees for overnight. After the reaction was complete, solvent was removed, and then ethyl acetate was added. The ethyl acetate solution was extracted three times with water. Organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50% ethyl acetate in hexane for 20 min) gave N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide.