Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 6-chloro-2-(bromoacetamido)benzoic acid from Example 42 (7 g, 0.024 mol), aniline (5.6 g, 6 mL, 250 mol %) and DMF (40 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled to rt, poured onto ice and the resulting crystalline product was solubilized by adding 5% KOH (70 mL, pH=9). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL), and the aqueous layer was acidified to pH=3 with 5% HBr and extracted with EtOAc (4×100 mL). Combined EtOAc washings were dried and concentrated. Recrystallization of the resulting solid from EtOAc/Hex, afforded 6 g (82%) of the title compound as white crystals, 176-178.2° C.; 1H NMR (DMSO-d6) δ 9.93 (s, 1H, COOH), 7.97 (d, 1H, J=8), 7.42 (t, 1H, J=8), 7.30 (d, 1H, J=7.6), 7.12 (t, 2H, J=7.2), 6.65 (t, 3H, J=7.2), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 170.19, 166.30, 148.15, 136.56, 131.12, 130.53, 128.98, 125.51, 121.39, 117.23, 112.71, 48.13; MS (EI, m/z) 304 (M+)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[OH:13])=[CH:8][CH:7]=1>C(O)C>[OH:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH:14]1[CH2:15][CH2:16][N:17]([CH2:3][CH2:2][C:1]#[N:4])[CH2:18][CH2:19]1
Reactant: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccccn2)CC1

Procedure:
2.3 ml (0.035 mol) of acrylonitrile are added dropwise to a solution of 10 g (0.035 mol) of α-(4-fluorophenyl)-α-(2-pyridyl)-4-piperidinemethanol in 60 ml of ethanol and 1 ml of Triton B.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:39])=[C:16]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[CH2:23][C:24](=[O:38])[NH:25][C:26]4[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:27]=4[C:28]=3[N:29]=2)[CH:17]=1)(C)(C)C>O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][C:22]3[CH2:23][C:24](=[O:38])[NH:25][C:26]4[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:27]=4[C:28]=3[N:29]=2)[C:15]([CH3:39])=[N:14][CH:13]=1
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncc(CCCN)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.7 %

Procedure:
To a 4M solution of HCl in dioxane (20 mL) was added tert-butyl[3-(6-methyl-5-{[6-oxo-9-(trifluoromethyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}pyridin-3-yl)propyl]carbamate (1.10 g, 2.04 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated to give 2-{[5-(3-aminopropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.35 g, 2.30 mmol, >99%) as a brown solid. LCMS (FA): Rt=0.55 min, m/z=443.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([S:32][CH3:31])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: C[S-]
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 130 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.120 g, 0.285 mmol) in 2 mL of DMF was added sodium thiomethoxide (0.100 g, 1.43 mmol). The mixture was heated in a sealed tube at 130° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.73-8.63 (m, 2H), 8.39 (s, 1H), 8.29-8.19 (m, 1H), 8.09 (s, 1H), 7.32-7.26 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 4.61 (br s, 1H), 4.50 (s, 2H), 4.05 (br s, 1H), 2.53 (s, 3H), 2.40-2.27 (m, 2H), 2.13-1.75 (m, 3H), 1.55-1.35 (m, 3H).
Reaction SMILES: ClC1C(F)=C(C=CC=1)CNC([C@@H]1C[C@]2(CO)[C@@H](C2)N1C(=O)[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=O.C(O[C:41]([N:43]1[CH2:47][C@@:46]([F:49])([CH3:48])[CH2:45][C@H:44]1[C:50](=[O:63])[NH:51][C@@H:52]([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:56]=1[F:62])[CH2:53][OH:54])=[O:42])(C)(C)C.ClCl.CCOC(C)=O>>[Cl:61][C:57]1[C:56]([F:62])=[C:55]([C@H:52]([NH:51][C:50]([C@@H:44]2[CH2:45][C@:46]([F:49])([CH3:48])[CH2:47][N:43]2[C:41](=[O:42])[CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]2)=[O:63])[CH2:53][OH:54])[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Agent: ClCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ncccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (2S,4R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9). White powder. TLC, Rf (CH2/Cl2/EtOAc 9:1)=0.60; MS (UPLC/MS): 519.3/521.3 [M+H]+, 563.3/565.3 [M+HCOO]−; tR (HPLC conditions a): 2.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccnc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=364.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-chloro-2-trifluoromethyl-pyrimidine.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CC1
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 2H), 6.57 (s, 1H), 4.05 (d, J=6.3 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.14 (m, 1H), 1.00 (t, J=7.3 Hz, 3H), 0.60 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 321 (M+1).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[C:22]1([CH3:30])[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:30][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: Cc1ccccc1C=O
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was suspended in 400 ml of toluene to which morpholine (3.5 g) and o-tolualdehyde (3.0 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.5 g of aldehyde was added. Reflux was continued for an additional six (6) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the pure product were concentrated and recrystallized from benzene/pentane to give 3.32 g of analytically pure product, m.p. 160°-162° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:45]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([NH2:45])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In a sealed tube a solution of Methyl (2R, 5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 12, 21.6 mg, 0.036 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day. The solvent was evaporated to dryness and the crude was purified by silica cartridge (2 g) (at first EtOAc and then 97.5:2.5 DCM/0.5 M NH3 in MeOH) to give 17.8 mg of the title compound as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (s, 1H) 7.70 (s, 2H) 7.28 (d, 1H) 7.15 (dd, 1H) 7.03 (d, 1H) 6.92 (dd, 1H) 6.78 (t, 1H) 5.31 (q, 1H) 4.14 (dd, 1H) 3.47 (t, 1H) 3.27-3.38 (m, 1H) 2.75 (s, 3H) 2.76 (t, 1H) 2.32 (s, 3H) 2.05-2.15 (m, 1H) 1.68-1.85 (m, 3H) 1.52-1.68 (m, 3H) 1.47 (d, 3H) 1.39-1.54 (m, 1H). NMR analysis revealed the presence of a large amount of DCM (˜55% w/w). HPLC: Rt 4.90 mins. This batch was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Br[C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=O>>[Br:20][C:17]1[CH:16]=[C:13]2[C:12](=[CH:19][CH:18]=1)[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[N:10]=[CH:14]2
Reactant: O=Cc1cc(Br)ccc1Br
Reactant: COc1ccccc1NN
Product: COc1ccccc1-n1ncc2cc(Br)ccc21

Procedure:
In analogy to Example 187, step 1, 2-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a brown oil. MS (m/e)=303.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([C:34]([F:37])([F:36])[F:35])[CH2:31][C@H:30]([NH:38]C(=O)OC(C)(C)C)[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2.Cl>O1CCOCC1.CO>[NH2:1][C:2]1[C:3]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[N:28]2[CH2:33][C@H:32]([C:34]([F:37])([F:36])[F:35])[CH2:31][C@H:30]([NH2:38])[CH2:29]2)=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH:6]=2
Reactant: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](N)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then evaporated under vacuum. The resulting residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C27H33F3N7O [M+H]+: m/z=528.3. found: 528.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:17][CH3:18])[CH:5]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[CH3:18][O:17][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)COc1ccc(CCO)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetate (1.53 g) in dichloromethane (30 ml) were added triethylamine (1.26 ml) and p-toluenesulfonyl chloride (1.26 g), and the mixture was stirred for 24 hours at room temperature. The reaction mixture was washed with 1N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave ethyl 2-[2-methoxy-4-[2-(p-toluenesulfonyloxy)ethyl]phenoxy]acetate (2.04 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.BrC[CH2:21][CH2:22][Cl:23].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C.O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:21][CH2:22][Cl:23])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: ClCCCBr
Reactant: COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: ClCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 76.2 %

Procedure:
The title compound was prepared from 3-chloro-2-(4-methoxy-phenyl)-2H-indazole (1.2 g, 4.9 mmol) and 1-bromo-3-chloropropane (3.1 g, 19.6 mmol), K2CO3 (2.8 g, 20.4 mmol), in methyl ethyl ketone (50 mL) was refluxed for 36 h. After the reaction mixture was diluted with water, the resulting aqueous mixture was extracted with ethyl acetate and sequentially washed with water, saturated aq. NaHCO3, water and brine. The combined organic portions were dried over Na2 SO4, filtered and concentrated in vacuo to afford the title compound (1.2 g, 80%). MS (APCI) m/z: 321 (M+1, 100).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.05 min; [M+H]+=418.95.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C=CC=CC=1>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of hydroxylamine hydrochloride (13 mg, 0.18 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 59, 62 mg, 0.12 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 3/7 hexanes/ethyl acetate eluted to 8/2 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (51 mg, 80%) as a white foam: EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307, found 529.0308.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][CH3:45]>>[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][C@H:18]2[C:16]([NH:15][C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:44]([CH2:43][C:39]2[O:38][CH:42]=[CH:41][CH:40]=2)[CH3:45])=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CNCc1ccco1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: CN(CC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1)Cc1ccco1

Procedure:
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-furyl-N-methylmethanamine, the title compound was obtained in 98.2% purity by HPLC.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([C:4]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:3]=1[CH2:2][O:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:31])[CH:14]=1)#[N:6]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Reactant: N#Cc1cc(F)ccc1CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3C#N)cc2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 2-(bromomethyl)-5-fluorobenzonitrile (4.31 g, 20.1 mmol) and methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (5.00 g, 18.3 mmol) in DMF (20 mL) was added K2CO3 (3.00 g, 22.0 mmol). The reaction was allowed to warm to RT and stirred overnight. Additional 2-(bromomethyl)-5-fluorobenzonitrile (0.39 g, 1.83 mmol) and K2CO3 (0.25 g, 1.83 mmol) were added and the reaction heated at 60° C. for 2 h. Solvent removed by distillation. Reaction neutralized with 5% citric acid (50 mL). Organic products were extracted in DCM (3×25 mL), dried over Na2SO4, filtered, and concentrated to a thick dark brown oil. Purified by silica gel flash column chromatography using EtOAc as the eluent to give the product as a brown solid, dried in vacuo (6.18 g, 76%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.76 (m, 2H), 7.66 (m, 1H), 7.52 (m, 2H), 6.24 (s, 1H), 6.09 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 407.1408 (M+H calculated for C23H20FN2O4 requires 407.1402).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH2:33][NH:34][C:35]([NH:37][C:38]3[N:42]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)[N:41]=[C:40]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=3)=[O:36])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.CC(O)C>CCO>[P:1]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH2:33][NH:34][C:35]([NH:37][C:38]3[N:42]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)[N:41]=[C:40]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=3)=[O:36])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)([OH:8])([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of di-tert-butyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethyl phosphate (3.66 g, 4.89 mmol) in EtOH (0.2M, 24 mL) was treated with SN HCl/iPrOH (2.93 mL, 14.7 mmol) at room temperature. Stirring at room temperature was continued overnight. The solvent was evaporated in vacuo, and the residue was coevaporated from toluene, and ether (2×). The beige foam was taken in MeOH and poured slowly into a beaker containing water. The precipitated solids were collected by filtration to provide 2.83 g (91%) of the desired product. MS (APCI+) m/z 637 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.00 (s, 1H), 7.71 (d, 1H, J=9 Hz), 6.88-7.37 (m, 10H), 6.24 (s, 1H), 4.61 (br, 1H), 4.28 (d, 2H, J=5.7 Hz), 4.19 (dd, 2H, J=5.2 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Cc1cccc(C)c1N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(2,6-dimethylphenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,6-dimethylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.