Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH3:17])=[C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:20]I.[Cl-].[NH4+]>CN(C=O)C>[C:1]([N:4]([C:5]1[CH:6]=[CH:7][C:8]([O:16][CH3:17])=[C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:10]=1)[CH3:20])(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)cc1C1OCCO1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C(C)=O)cc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
A solution of 2-(5-acetylamino-2-methoxyphenyl)-1,3-dioxolane (5.0 g, 21.1 mmol) in DMF (16 ml) was added to a suspension of NaH (1.0 g, 25.3 mmol) in DMF (5 ml) and then the mixture was stirred at room temperature for 10 min. To the mixture was added methyl iodide (3.6 g, 25.3 mmol) and then stirred at room temperature for 1 hr. And to the resulted reaction mixture was added ammonium chloride and then extracted with CH2Cl2. The extract was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give crude 2-[5-(N-acetyl-N-methylamino)-2-methoxyphenyl]-1,3-dioxolane (5.0 g, 94%) as a orange oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:6]=1.[CH3:17][C:18]1[O:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)CCO>CC#N>[CH3:17][C:18]1[O:22][C:21]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)[CH:6]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(B(O)O)o1
Reactant: CC(=O)Nc1cccc(-n2cnc(Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCCCO
Solvent: CC#N
Product: CC(=O)Nc1cccc(-n2cnc(-c3ccc(C)o3)c2)c1
Temperature: 170 °C
Yield: 11.4 %

Procedure:
A slurry of 12 (140 mg; 0.5 mmol), 5-methylfuran-2-boronic acid (88.1 mg; 0.7 mmol), Cs2CO3 (179 mg, 0.55 mmol) and propane-1,3-diol (53 mg; 1.4 mmol) in CH3CN (4 mL) was purged with argon and Cl2Pd(PPh3)2 (7 mg; 2 mol %) was added. The mixture was heated in EmrysOptimiser (170° C., 15 min). The reaction mixture was filtered hot through a fritte and the precipitate was extracted with hot CH3CN (8 mL), which was filtered through the same fritte and pooled with the first fraction. The yellow solution was evaporated to dryness and redissolved in 1 mL CH3CN which was purified by preparative LC-MS to give pure title compound 16 mg (11%). HRMS (ESI+): m/z=281.3135 [M+H]
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH:46]1[CH2:48][CH2:47]1)[C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][N:9]1[S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:35])=[O:34])=[O:7])#[N:2].[NH4+].[Cl-].[N-:51]=[N+:52]=[N-:53].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH:46]1([N:5]([CH2:4][CH2:3][C:1]2[NH:53][N:52]=[N:51][N:2]=2)[C:6]([C@@H:8]2[CH2:12][C@@H:11]([S:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][N:9]2[S:33]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)(=[O:35])=[O:34])=[O:7])[CH2:47][CH2:48]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCN(C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C([C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)N(CCc1nnn[nH]1)C1CC1
Yield: 40 %

Procedure:
A solution of 336 mg (0.5 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid (2-cyano-ethyl)-cyclopropyl-amide, 267 mg (5 mmol) NH4Cl and 325 mg (5 mmol) NaN3 in 10 ml DMF were heated at 70° C. for 22 h. 267 mg (5 mmol) NH4Cl and 325 mg (5 mmol) NaN3 together with 40 ml DMF were added and heated at 100° C. (24h) and at 120° C. (24h). The reaction was poured in H2O (0° C.)/EtOAc (3×). The organic phases were washed with aqueous 10% KHSO4, 10% NaCl solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (CH2Cl2/MeOH: 99:1) gave 143 mg (40%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid cyclopropyl-[2-(1H -tetrazol-5-yl)-ethyl]-amide, MS: 715 (MH+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:25]>O>[Br:25][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cc2)CC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(C)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of N-(1-(4-aminophenyl)piperidin-4-yl)-N-methylacetamide (479.7 mg, 1.94 mmol) in 6 mL of aq HBr was added a solution of NaNO2 (147 mg, 2.13 mmol) in 2 mL of H2O at 0° C., then the mixture was stirred at 0° C. for 40 minutes. After that, the mixture was poured into a solution of CuBr (584 mg, 4.07 mmol) in 6 mL aq HBr at 0° C., the reaction was heated to 60° C. and stirred for 2 hours. After cooling, the mixture was based with 2M NaOH to pH=8-9 and extracted with EA, washed with H2O and brine, dried and concentrated to give black solid. MS (m/z): 313 (M+H)+
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1.[CH3:10][NH2:11]>>[CH3:9][CH:5]1[CH:6]([CH3:8])[O:7][CH:3]([CH2:2][NH:11][CH3:10])[O:4]1
Reactant: CN
Reactant: CC1OC(CBr)OC1C
Product: CNCC1OC(C)C(C)O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (100 grams) and 40% aqueous methylamine (300 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and were stirred at room temperature for a period of about 14 hours. The reaction mixture was then extracted with diethyl ether. The extract was dried and the ether stripped off using a rotary evaporator to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)methylamine as the residue.
Reaction SMILES: [CH:1]([O:4][CH:5]([C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1)[C:6]#[N:7])([CH3:3])[CH3:2].N>CO.[Ni]>[CH:1]([O:4][CH:5]([C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1)[CH2:6][NH2:7])([CH3:3])[CH3:2]
Reactant: Cc1ncc(C(C#N)OC(C)C)cn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ncc(C(CN)OC(C)C)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (169 mg, 0.884 mmol) was dissolved in methanol (10 ml) and 7M NH3 in methanol (4 ml). Argon was bubbled through the solution for 5 minutes. To the reaction was added Raney nickel (100 mg, 1.704 mmol) and it was fitted with a H2-filled balloon. After stirring at room temperature for 20 hours LCMS shows only around 30% conversion and raney nickel (100 mg, 1.70 mmol) was added. The reaction was stirred for another 72 hours, then filtered through a plug of celite and concentrated in vacuo. The crude product used for next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].[CH3:18][N:19]([CH:21](OC)OC)[CH3:20]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[O:13])/[CH:12]=[CH:18]/[N:19]([CH3:21])[CH3:20])[CH:8]=[CH:7][C:6]=1[S:14]([CH3:17])(=[O:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(C)=O)ccc1S(C)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Yield: 27.7 %

Procedure:
A solution of 5-acetyl-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.8 mmol) and DMF-DMA (1.2 g, 10 mmol) in DMF (20 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1-2:1) to give the title compound (0.5 g, 30%). [M+H] Calc'd for C13H17NO4S, 284. Found, 284.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br>CC(C)=O>[CH3:31][O:32][C:33](=[O:36])[CH2:34][N:14]1[CH2:15][CH2:16][C:17]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:12][CH2:13]1
Reactant: COC(=O)CBr
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 1 mmol) in acetone (3 mL) was added Na2CO3 (2 mmol) and bromoacetic methyl ester (2 mmol). The mixture was stirred at RT for 1 h. After concentration and purification (SiO2, 2 M NH3 in MeOH/CH2Cl2), the title compound was obtained (60 mg). MS (ESI): exact mass calculated for C23H24ClN3O2, 409.16. found, m/z 410.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.42 (m, 2H), 7.31-7.29 (m, 2H), 7.25-7.23 (br m, 2H), 7.20-7.18 (br m, 1H), 7.02-6.99 (br m, 2H), 5.26 (s, 2H), 3.64 (s, 2H), 3.41 (s, 2H), 2.81-2.79 (br m, 4H), 2.75-2.73 (br m, 2H), 2.70-2.68 (br m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH3:11].N1C=CC=CC=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:20])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1Br
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(CCl)ccc1Br

Procedure:
4-Bromo-3-methoxybenzyl alcohol (21.7 g, 0.1 m) dissolved in toluene (200 ml) containing pyridine (11.8 g, 0.15 m) is stirred at 5° and treated wiih thionyl chloride (23.8 g, 0.2 m). The mixture is stirred, diluted with water and the organic layer washed with dilute hydrochloric acid, dried and concentrated in vacuo to give 4-bromo-3-methoxybenzyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].CO>>[ClH:35].[CH3:34][O:33][C:17]1[C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[S:21][C:22]=2[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Yield: 57 %

Procedure:
0.15 g (0.31 mMol) 4-{4-methoxy-2-[(2-methyl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 4 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 5 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 80 mg (57%) N-(4-methoxy-7-piperdin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide hydrochloride (1:2) as a white solid. F.p.: 272-277° C.
Reaction SMILES: Cl[Sn]Cl.[Cl:4][C:5]1[C:15]2[CH2:14][O:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[Cl:4][C:5]1[C:15]2[CH2:14][O:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[CH:20][C:21]3[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1
Agent: Cl[Sn]Cl
Product: Nc1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1

Procedure:
Prepare the title compound by SnCl2 reduction of 7-chloro-11-(3-nitro-benzylidene)-6,11-dihydro-dibenzo[b,e]oxepine (from Example 272) to provide 900 mg (98%) of product.
Reaction SMILES: N1CCOC[CH2:2]1.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:9]=1[CH2:10][CH2:11][C@H:12]2[O:18][C:19]1[CH:31]=[CH:30][C:22]2[C@H:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1.Cl>CO>[CH3:2][O:28][C:27](=[O:29])[CH2:26][C@H:23]1[C:22]2[CH:30]=[CH:31][C:19]([O:18][C@H:12]3[C:13]4[C:9](=[C:8]([Br:7])[CH:16]=[CH:15][C:14]=4[F:17])[CH2:10][CH2:11]3)=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: C1COCCN1
Agent: Cl
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.87 g (11.9 mmol) [(S)-6-((R)-4-bromo-7-fluoroindan-1-yloxy)-2,3-dihydrobenzo-furan-3-yl]-acetic acid morpholine salt is suspended in 22 ml MeOH. Then, 3.56 ml (14.2 mmol) HCl (4 M in dioxane) is added and the funnel is rinsed with 1.50 ml MeOH. The mixture is stirred overnight at r.t. and seeds are added. After 30 min, 5.90 ml water is added and stirring is continued. The precipitated product is filtered off, washed with 14.6 ml MeOH/water (4:1) and dried. Yield: 4.25 g; Rf=0.39 (silica gel, PE/EtOAc=8/2); Mass spectrum (ESI): m/z=421 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.Cl[C:23]1[CH:28]=CC=C(Cl)[CH:24]=1>>[CH3:1][C:2]1[C:6]2[C:7]([OH:18])=[C:8]([CH2:28][CH:23]=[CH2:24])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1
Agent: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12
Product: C=CCc1cc(C(=O)c2cccs2)c2occ(C)c2c1O

Procedure:
A solution of 3-methyl-4-allyloxy-7-(2-thienoyl)benzofuran (0.43 g, 1.44 mmol) in 1,3-dichlorobenzene (4 mL) was heated to reflux under nitrogen for five hours. The reaction mixture was cooled and the product purified by preparative HPLC, using 10% ethyl acetate in hexane as eluant, to afford 3-methyl-4-hydroxy-5-(2-propen-1-yl)-7-(2-thienoyl)benzofuran, compound 4. An analytical sample was obtained by recrystallization from ether/hexane. 1H NMR d 2.43 (3H, d, J=2 Hz), 3.54 (2H, d, J=6 Hz), 5.30 (2H, m), 5.86 (1H, s), 6.10 (1H, m), 7.16 (1H, dd, J=4 Hz, 4 Hz), 7.34 (1H, d, J=2 Hz), 7.50 (1H, s), 7.65 (1H, d, J=4 Hz), 7.72 (1H, d, J=4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16](O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C:16]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:19])[N:17]=1
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCCC2
Temperature: 25 °C

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ol (500 mg, 1.89 mmol) in POCl3 (6 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to afford a white solid which was dissolved in methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid 4-Chloro-2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline which was not further purified.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=O)[CH3:2]>O=P(Cl)(Cl)Cl>[CH3:2][C:1]1[O:16][C:6]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Yield: 8.8 %

Procedure:
A solution of 4-nitro-benzoic acid N′-acetyl-hydrazide (200 mg, 8.9 mmol) in distilled POCl3 (4 mL) was refluxed at 110° C. under nitrogen for 6 hours. The reaction mixture was concentrated and the residue was quenched with 10% NaOH solution. The resulting precipitate was collected by filtration to afford 160 mg (89%) of 2-Methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole. 1H NMR: (CDCl3): δ 8.38 (d, 2H), 8.24 (d, 2H), 2.7 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:18]=3[CH:35]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:36]OC(=O)C1C=CC(N)=CC=1Cl>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:24])=[O:25])[C:18]=3[CH:35]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1Cl

Procedure:
2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=534.9, 536.9 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-chloro-benzoic acid methyl ester and yielded 2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (301 mg, 72%).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([F:9])[C:5]([F:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[C:15]([O:17][CH3:18])=[O:16].CS(C)=O.[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>O>[CH3:24][C:23]([NH:28][C:7]1[C:2]([F:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([F:10])[C:6]=1[F:9])([CH3:25])[CH2:26][CH3:27]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Reactant: CCC(C)(C)N
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C)Nc1c(F)c(F)c(C(=O)OC)c(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5,6-Tetrafluoro-1,2-benzenedicarboxylic acid, dimethyl ester (Example 1), 2.66 g, is treated with 8 g of dimethylsulfoxide and the mixture is warmed to dissolve the solid. The solution is cooled in an ice bath and 2.65 g of tertiary-pentylamine is added. The resulting solution is then stirred at room temperature for three hours, 50 ml of water added, and the solution extracted with heptanes (2×30 ml). The combined heptane extract is extracted with a 5% aqueous solution of hydrochloric acid (2×4 ml) and concentrated to give 4-[(1,1-dimethylpropyl)amino]-3,5,6-trifluoro-1,2-benzenedicarboxylic acid, dimethyl ester as an oil. Hydrochloric acid (36% aqueous solution), 20 ml, is added to this oil and the resulting mixture is heated at reflux for 20 hours. The solution is concentrated to 4-5 ml and then diluted with water (20 ml). Cooling gave crystals which are collected and vacuum dried to give 1.2 g of 3-amino-2,4,5-trifluorobenzoic acid (63%); mp 133° -136° C.; GC (97.9%); HPLC (94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[Cl:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1)[C:19]#[N:20]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(C#N)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 42.7 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211 mg, 1 mmol), 4-amino-3-chlorobenzonitrile (305 mg, 2 mmol), cesium carbonate (0.65 g, 2 mmol), XantPhos (17 mg, 0.03 mmol) and Pd2(dba)3 (5 mg, 0.02 mmol) in dioxane (3 mL) was sonnicated in an ultrasonic bath for 1 min. The mixture was then degassed under a stream of nitrogen for 5 min. The tube was sealed and the reaction was heated at 100° C. for 18 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL). The organic layer was washed with water (2×20 mL) and the combined aqueous extracts were further washed with ethyl acetate (2×15 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile as a white solid (140 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 8.85 (d, J=8.8, 1H); 8.23 (d, J=1.1, 1H); 7.80 (s, 1H); 7.68 (d, J=1.9, 1H); 7.58-7.53 (m, 1H); 5.32 (s br, 1H); 3.11 (d, J=4.7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[C-:11]#[N:12].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: [C-]#N
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na2S2O5 in 300 ml of water is stirred overnight at RT. The reaction mixture is cooled to 0° C., a solution of 52 g of KCN in 100 ml of water is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 76 g of the expected product, which is used as such.