Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].OS(O)(=O)=O.[C:16]([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(=O)O)cc1Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-5-methylthiophene-2-carboxylic acid (45 g, 204 mmol) in methanol (225 mL) was added concentrated H2SO4 (4.0 g, 41 mmol). The reaction mixture was heated to reflux overnight, cooled to room temperature, poured into saturated NaHCO3 (800 mL), and left to stir for 30 min. The precipitate was filtered, washed with water, and dried under high-vacuum to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H); 3.88 (s, 3H); 2.45 (s, 3H). LRMS (APCI) calc'd for (C7H8BrO2S) [M+H]+, 234.9. found 234.9.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[CH3:100][O:101][C:102](=[O:111])[C:103]1[CH:108]=[CH:107][C:106]([CH2:109][NH2:110])=[CH:105][CH:104]=1>>[ClH:45].[CH3:100][O:101][C:102](=[O:111])[C:103]1[CH:108]=[CH:107][C:106]([CH2:109][NH:110][C:70]([NH:69][C@@H:66]2[CH2:67][CH2:68][N:64]([C:62]3[N:61]=[C:60]4[C:56]([N:57]=[CH:58][N:59]4[C@@H:80]4[CH2:84][C@H:83]([N:85]5[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]5)[C@@H:82]([OH:92])[C@H:81]4[OH:93])=[C:55]([NH:54][CH2:53][CH:52]([C:94]4[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:63]=3)[CH2:65]2)=[O:71])=[CH:105][CH:104]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccc(C(=O)OC)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxcyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-aminomethyl-benzoic acid methyl ester. MS (ES+) m/e 787.45 (MH+)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)(=[O:10])=[O:11])=[CH:17][CH:18]=2)=[O:23])=[CH:33][CH:32]=1)[CH3:38]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1

Procedure:
4 4-{[1-(3-Trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=503.0 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-trifluromethyl-benzenesulfonyl chloride, yielding 4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.CN(C=O)C.CS([C:21]1[N:22]=[C:23]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:24]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:27][CH2:26][C:25]=2[N:41]=1)(=O)=O>CO>[CH3:3][C:4]1([CH3:11])[O:8][C@@H:7]([CH2:9][O:10][C:21]2[N:22]=[C:23]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:45][CH:44]=3)[C:24]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:27][CH2:26][C:25]=3[N:41]=2)[CH2:6][O:5]1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)OC[C@H](COc2nc3c(c(Nc4ccc(C(F)(F)F)cc4)n2)CCN(c2ncccc2C(F)(F)F)CC3)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A dispersion of NaH in mineral oil (12.0 mg, 0.28 mmol) was added to a flask containing (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (116 μL, 0.94 mmol) and DMF (1.0 mL). After 30 min, the mixture was transferred to a flask containing [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 50 mg, 0.094 mmol). The resulting mixture was then heated at 70° C. for 24 h. The mixture was cooled, diluted with MeOH (1.0 mL) and purified by reverse phase HPLC, yielding 39 mg (70%) of the title compound. MS (ESI): mass calcd. for C27H27F6N5O3, 583.20; m/z found, 584.2 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69 (d, J=11.0 Hz, 2H), 7.59 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.68 (s, 1H), 4.52-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.90 (m, 1H), 3.63-3.56 (m, 4H), 3.18-3.15 (m, 2H), 2.96-2.93 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][CH2:4][O:5][C:6](=[O:47])[C@@H:7]([NH:39]C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:26][CH:25]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:48][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:47])[C@@H:7]([NH2:39])[CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CN(C)CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOC(=O)[C@@H](N)CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h
Yield: 137.2 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-4-(3-{3-[4-(pyridin-2-yloxymethyl)-benzyl]-isoxazol-5-yl}-pyridin-2-ylcarbamoyl)-butyric acid 2-dimethylamino-ethyl ester (53 mg, 0.060 mmol; purity of 75%) described in Manufacturing Example 3-2 and dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, which was stirred overnight at the same temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and the residue thus obtained was washed with diethyl ether, so as to obtain the titled compound (46 mg) as di-(trifluoroacetic acid) salt.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1.[Cl:20]C1C=CC=CC=1>>[Cl:6][C:1]1[C:2](=[O:3])[N:14]([CH2:13][C:12]2[CH:18]=[CH:19][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:15]=[C:16]([Cl:20])[N:17]=1
Reactant: COc1ccc(CNCC#N)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1ccccc1
Product: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Temperature: 90 °C
Yield: 27.6 %

Procedure:
Oxalyl chloride (17.5 ml, 200 mmol) was added dropwise via a dropping funnel to a mixture of compound (7) (8.5 g, 48.2 mmol) in chlorobenzene (60 ml). The reaction was heated at about 90° C. for about 16 h. The solvent was removed. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with Hex/EtOAc (10:1) to afford 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (4.0 g, 13.33 mmol, 27.6% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[S:20][C:19]([CH3:21])=[N:18][CH:17]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([N+:22]([O-])=O)[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[S:20][C:19]([CH3:21])=[N:18][CH:17]=2)[CH:11]=1)[CH3:2]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnc(C)s2)c1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(N)ccc1Oc1ccnc(-c2cnc(C)s2)c1
Temperature: 50 °C
Yield: 11.5 %

Procedure:
A mixture of 5-(4-((2-ethyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)-2-methylthiazole (756 mg, 2.208 mmol) and 10% Pd/C (50% w/w with water, 235 mg, 0.221 mmol) in MeOH (15 mL) was hydrogenated (1 atm) at RT overnight, then warmed to 50° C. for 4 h. The mixture was cooled to RT, the solids removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford 6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (79 mg, 11%). MS (ESI) m/z: 313.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C=O)CC1

Procedure:
To a stirring solution of 2-bromo-3-formylpyridine (XVI, EXAMPLE 1, 2.0 g, 10.80 mmol), and diisopropylethylamine (1.39 g, 10.80 mmol) in THF is added 1-(tert-butoxycarbonyl)-piperazine (Aldrich, 2.01 g, 10.80 mmol). The mixture is heated in a sealed tube at 100° for 16 hr, cooled to 20°-25° and poured into water (100 ml). The aqueous layer is extracted with ethyl acetate (100 ml), the organic layer separated, dried over sodium sulfate and solvent evaporated to dryness. The residue is purified via flash column chromatography (silica gel; hexane/ethyl acetate (4/1)) to give the title compound, mp 88°-89°; NMR (CDCl3) 1.48, 3.42, 3.60, 6.96, 8.01, 8.39 and 10.03δ; MS (EI, m/e) 291 (M+).
Reaction SMILES: [Na].[H-].[Na+].[OH:4][C:5]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].Cl[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[CH3:26].[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>CN1C(=O)CCC1.CCOCC>[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:14][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:13][C:5]=1[O:4][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COCCOCOC(=O)c1cc(Oc2c(C)cc([N+](=O)[O-])cc2C)ccc1OCOCCOC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium NaH (60% dispersion in mineral oil; 1.32 g, 33 mmol) in 50 mL of NMP is cooled to 0° C. and 2,5-dihydroxybenzoic acid (1.54 g, 10 mmol) is added in one portion. The mixture is warmed to room temperature, and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (2.41 g, 13 mmol) is added in one portion and the reaction is heated at 120° C. for 3 h. The reaction is cooled to RT and 2-methoxyethoxymethyl chloride (2.85 mL, 25 mmol) is added. After stirring for 30 min, the mixture is poured onto water and the product is taken up in Et2O. The organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated. Chromatography on silica (eluant; EtOAc/hexane-1/2→3/2) affords 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxyethoxymethoxy)benzoic acid 2-methoxyethoxymethyl ester: NMR (CDCl3) 2.23 (s, 6H), 3.36 (s, 3H), 3.38 (s, 3H), 3.54-3.60 (m, 4H), 3.80-3.90 (m, 4H), 5.28 (s, 2H), 5.52 (s, 2H), 6.82 (dd, 1H, J=9,3), 7.17-7.23 (m, 2H), 8.02 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[O:6]/[C:5]/2=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1.O.[NH2:32][NH2:33]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:6])[NH:33][N:32]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)c(Cl)cc43)ccc2F)CC1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cc(Cl)c(Cl)cc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
(Z)-5,6-dichloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (64) (127 mg, 0.28 mmol) was taken up in water (2 mL) and N,N-dimethylformamide (0.500 mL). The resulting mixture was treated with hydrazine hydrate (0.080 mL, 1.65 mmol) and the reaction was heated to 105° C. with stirring for 90 minutes. The reaction mixture was cooled, diluted with water (˜10 mL) and solid collected by suction filtration to afford the crude product, which was purified by flash silica chromatography, eluting with neat ethyl acetate. Pure fractions were evaporated to dryness and the residue triturated under diethyl ether and dried under vacuum to afford the desired material as a white solid (46.0 mg, 35% yield); 1H NMR (400.132 MHz, DMSO) δ 1.30-1.40 (1H, m), 1.44-1.53 (1H, m), 1.72-1.79 (1H, m), 1.87-1.94 (1H, m), 3.04-3.11 (1H, m), 3.29 (3H, s), 3.30-3.40 (2H, m), 3.44-3.49 (1H, m), 3.92-4.00 (1H, m), 4.37 (2H, s), 7.26 (1H, t), 7.38-7.45 (2H, m), 8.29 (1H, s), 8.40 (1H, s), 12.83 (1H, s); m/z (LC-MS, ESI+), RT=2.13 (M+H 464 & 465.9).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH:32]=[C:31]([CH3:30])[CH:35]=[N:34]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 294 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 4-Methyl-1H-pyrazole (43%yield, white solid, MS (m/e): 493.1 (M+H, 100%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>CN(C)C=O>[CH3:9][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:24][CH2:21][C:22]#[CH:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20]
Reactant: C#CCN
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a solution of 1.820 g (6.00 mmol) of of [(4-fluoro-benzenesulfonyl)-methyl-amino]-acetic acid tert-butylester in 25 mL of dimethylformamide was added 5.0 mL (4.0 g, 72.89 mmol) of propargylamine. The mixture was heated to 80° C. and stirred for 48 h. The mixture was partitioned between 400 mL of dichloromethane and 200 mL of 20% aqueous NH4Cl solution. The organic layer was separated, washed with 200 mL of water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Silica gel column chromatography of the residue, eluting with 1% MeOH/CH2Cl2, provides 1.067 g (53%) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid, tert-butyl ester as a light brown oil. Electrospray Mass Spec 339.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4CCN(C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:36])[CH:3]=1.[Cl:37]C1C=CC(N)=C(F)C=1.[CH3:46][CH:47](O)[CH3:48]>>[ClH:37].[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([NH:6][C:5]3[CH:34]=[CH:35][C:2]([Cl:37])=[CH:3][C:4]=3[F:36])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18])[C:21]1[CH:48]=[CH:47][CH:46]=[CH:23][CH:22]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Product: Cl
Yield: 64 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2 g, 4 mmol), (prepared as described in WO 97/22596, Example 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in 2-propanol (40 ml) was heated at reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol then ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 64%).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[N:5]=[CH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[C:7]4[O:8][CH2:9][CH2:10][NH:11][C:6]=4[N:5]=[CH:4][N:3]=3)[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1.[C:14]([OH:16])([C:13]([F:18])([F:17])[F:12])=[O:15]
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: Clc1ncnc2c1OCCN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc5c4OCCN5)CC3)n2)cc1C(F)(F)F
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (30.0 mg; 0.17 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (109.2 mg; 0.17 mmol; 1.0 eq.) and cesium carbonate (227.8 mg; 0.7 mmol; 4.0 eq.) in 1 ml of DMSO was stirred at 120° C. for 48 hrs. The reaction mixture was purified by pre-HPLC to afford the title compound as TFA salt (48.6 mg, 43% yield); LC-MS (M+H=532, obsd.=532);
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:14])[C:11]([OH:13])=O)[CH:3]=1.[CH:15]([N:18]([CH:21]([CH3:23])C)CC)([CH3:17])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:14])[C:11](=[O:13])[N:18]2[CH2:15][CH2:17][CH2:23][CH2:21]2)[CH:3]=1
Reactant: O=C(O)C(=O)NNc1cc(I)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(NNc1cc(I)ccn1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a solution of [2-(4-iodopyridin-2-yl)hydrazino](oxo)acetic acid (0.64 g, 2.10 mmol) in di-methylformamide (21 mL) was added diisopropylethylamine (1.65 mL, 9.47 mmol), pyrrolidine (0.74 mL, 8.84 mmol) and finally HATU (2.40 g, 6.31 mmol). The resulting mixture was stirred at room temperature under argon atmosphere for 18 hours. The solvent was removed under reduced pressure, water was added and it was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The crude was purified by reverse phase chromatography on a silica C18 cartridge eluting with water/acetonitrile:methanol (1:1), using a gradient from 100% water to 100% acetonitrile:methanol (1:1), to yield the title compound (0.26 g, 30%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nn1ccc2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of pyrrolo[3,2-b]pyridine (1.64 mmol) and potassium tert-butoxide (3.29 mmol) in DMF (7.3 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl. in ether (16.3 mL) is added drop-wise at rt and the reaction mixture is stirred at rt for 3 h. The reaction mixture is quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The combined organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford pyrrolo[3,2-b]pyridin-1-ylamine (136 mg, 62%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.89 (br, 2N—H), 6.61 (d, H), 7.16 (m, H), 7.38 (d, H), 7.76 (d, H), 8.47 (d, H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:33][NH2:34])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:34]/[NH:33][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: NNC(=O)c1cccnc1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: C/C(=N\NC(=O)c1cccnc1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 64.2 %

Procedure:
The title compound (17.0 mg, 59%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and nicotinic acid hydrazide (17.0 mg, 0.12 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.64, 11.38 (bs, 1H), 9.52 (s, 1H), 9.05 (s, 1H), 8.93 (dd, 1H), 8.78 (d, 1H), 8.42 (d, 1H), 8.20 (d, 1H), 7.84 (d, 1H), 7.56 (m, 2H), 6.26 (s, 2H), 2.49 (s, 3H). LCMS (method A): [MH]+=442, tR=2.10 min.
Reaction SMILES: C[O:2][C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1.Br>O>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:27][N:28]=[N:29][N:30]=4)=[CH:18][CH:19]=3)[C:3](=[O:2])[NH:4][C:5]=12
Reactant: COc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Br
Solvent: O
Product: Cc1ccnc2c1[nH]c(=O)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
A mixture of 90 mg (0.23 mmol) of 2-methoxy-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine and 1 ml of 48% HBr was stirred at a room temperature for 1.5 hours. The product mixture was mixed with water to produce crystals, which was taken out and washed with water to obtain 70 mg of the intended compound.