Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccccc1Oc1ccccc1
Yield: 82.3 %

Procedure:
Into a three-necked 300 ml round bottom flask are charged 10 g (0.038 mole) of 2-(2-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane and 50 ml of dimethyl sulfoxide. To this mixture with stirring is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. Reaction mixture is heated to give 60° for two hours and then poured into water and extracted with hexane. Combined hexane extracts are washed with water and dried over MgSO4. Solvent is evaporated under vacuum to give 11.2 g of product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])=[O:3].O1CCOCC1.[H-].[Na+].C(O)(=O)C.C([O:29][C:30](=O)[C:31]([CH3:35])([CH3:34])[C:32]#[N:33])C>>[CH3:34][C:31]([CH3:35])([C:30](=[O:29])[CH2:1][C:2](=[O:3])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[OH:14])[C:32]#[N:33]
Reactant: CCOC(=O)C(C)(C)C#N
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(O)c(C(=O)CC(=O)C(C)(C)C#N)c(OC)c1
Temperature: 0 °C

Procedure:
A mixture of 73.5 g of 2-hydroxy-4,6-dimethoxyacetophenone, 260 g of dimethylcyanoacetic acid ethyl ester and 375 ml of absolute dioxane is introduced into a suspension of 28.6 g of NaH in 7.3 g of dimethylcyanoacetic acid ethyl ester at 0°-10°, while stirring. The mixture is heated for 1 hour at 80°, cooled and poured into acetic acid and the resulting solution is stirred into ice water to give 2,2-dimethyl-3,5-dioxo-5-(2-hydroxy-4,6-dimethoxyphenyl)-pentanonitrile; m.p. 112°-113°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]([C:21]1(Br)[CH2:24][CH2:23][CH2:22]1)=[O:20]>CN(C=O)C.COC(C1(Br)CCC1)=O>[CH3:17][O:18][C:19]([C:21]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Temperature: 140 °C
Yield: 104.7 %

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol), KI (3 g) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol). The mixture was heated at 140° C. for 1.5 h. Then additional 1-bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated to give the title compound as dark oil (18 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>CO.C(Cl)Cl>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2C1
Yield: 17.6 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.26 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (88 mg, 0.26 mmol) were coupled to provide 2-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide (25 mg, 18%) as a pale yellow solid following preparative tlc (10% MeOH-DCM); NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.44 (d, J=8 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.37 (m, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 3.76 (s, 2H), 3.43 (s, 2H), 2.77 (m, 8H), 1.22 (t, J=7 Hz, 3H); MS (m/e) 546 (M+1); mp 175° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:36][CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:39][CH2:38][CH2:37][Cl:36])=[O:31])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NCCCl
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (66 mg, 0.15 mmol) synthesized in Example (66g), 2-chloroethylamine hydrochloride (34 mg, 0.30 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were dissolved in dichloromethane (10 mL), and WSCI•HCl (31 mg, 0.16 mmol) was added at room temperature, followed by stirring for 1 hour under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (56 mg, yield 79%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:29]4[O:28][C:27]([C:30]([NH2:32])=O)=[CH:26][C:25](=[O:33])[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:29]4[O:28][C:27]([C:30]#[N:32])=[CH:26][C:25](=[O:33])[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Yield: 97 %

Procedure:
Following the process described in example 2 (point D), by reacting 8-[(E)-2-[4-(4-phenylbutoxy)phenyl]-ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide with phosphorous oxychloride in DMF for 0.5 h at 0° C., the title compound was prepared (97% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH2:26]([NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Product: CCNC(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cc1

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-ethylaminocarbonyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=1.26 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.NN.C(O)C>O>[NH2:24][C:19]1[CH:18]=[C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c2c1C
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(N)c3)c2c1C
Temperature: 85 °C
Yield: 101.8 %

Procedure:
Using a procedure similar to Tet. Lett. 1990, 1181-1182, Montmorillinite K10 clay (425 mg) was added to a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.608 g, 1.42 mmol), anhydrous hydrazine (0.276 μL, 8.95 mmol) and ethanol (4.2 mL) and the suspension was heated at 85° C. for 30 min. The reaction mixture was cooled to room temperature, added to water and extracted with ether. The ether was dried and concentrated to provide the title compound as a white solid (0.576 g, 100%): mp 173-175° C.: NMR (DMSO-d6); δ 9.26 (s, 1H), 8.14 (dd, J=8, 1 Hz, 1H), 7.63-7.58 (m, 2 H), 7.42 (ddd, J=8, 6, 1 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.35 (dd, J=8, 2 Hz, 1H), 4.67 (broad s, 2H), 2.42 (s, 3H), 1.69 (s, 3H); MS (+FAB): 1 bromine isotope pattern 398 (30%, M+H), 400 (30%, M+H); Anal. Calc. for C20H16BrNOS: C, 60.31, H, 4.05, N, 3.52; Found: C, 61.36, H, 4.08, N, 3.25.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Into a 3 L 4-necked round-bottom flask under nitrogen was placed a solution of 3-nitro-1H-pyrazole (100 g, 884.37 mmol, 1.00 equiv.) in THF (1.5 L), followed by the addition of NaH (53 g, 1.32 mol, 1.50 equiv, 60% suspension) batchwise at 0° C. The resulting solution was stirred at 0° C. for 1 h. A solution of [2-(chloromethoxy)ethyl]trimethylsilane (117.4 g, 704.17 mmol, 1.20 equiv) in THF (500 mL) was then added dropwise with stirring at 0° C. The resulting solution was stirred at 25° C. for 1 h, quenched by the addition of EtOH (200 mL), concentrated under vacuum and diluted with 2 L of EtOAc. The resulting mixture was washed with 2×1 L of brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with 200 mL of petroleum ether. The solids were collected by filtration and washed with petroleum ether (2×500 mL) to afford 125 g (52%) of 3-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.O=C1C2C(=CC=CC=2)C(=O)[N:9]1[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[CH:26][C:27]=2[O:29][CH3:30])[C:22]([NH:33][C:34]2[S:35][CH:36]=[C:37](C(O)=O)[N:38]=2)=[CH:21][N:20]=1.[CH3:42][N:43]([CH:45]=[O:46])C.CN>ClCCl>[CH3:42][NH:43][C:45]([C:37]1[N:38]=[C:34]([NH:33][C:22]2[C:23]3[C:28](=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[C:19]([CH2:18][NH2:9])=[N:20][CH:21]=2)[S:35][CH:36]=1)=[O:46]
Reactant: COc1cc(OC)c2c(CN3C(=O)c4ccccc4C3=O)ncc(Nc3nc(C(=O)O)cs3)c2c1
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1csc(Nc2cnc(CN)c3c(OC)cc(OC)cc23)n1
Reaction time: 1 h
Yield: 60 %

Procedure:
Oxalyl chloride (8 μL, 0.092 mmol) was added to a solution of Example 49A (30 mg, 0.061 mmol) in dichloromethane (4 mL). Catalytic DMF was added, and the reaction stirred for 1 h. Methylamine (180 μL, 2M in THF, 0.366 mmol) was added, and the reaction stirred for 30 min. Organics were washed with brine, dried (MgSO4) and concentrated. Deprotection was carried out with hydrazine (0.2 mL) in methanol (3 mL), stirring for 1 h. Purification by Prep-HPLC gave 17.8 mg (60%) of the title compound (TFA salt) as a yellow solid. H1-NMR (MeOD-d4): δ 9.16 (s, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 4.83 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 2.91 (s, 3H). MS (ES) (M+H) calc'd for C17H19N5O3S, 374; found 374.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([O:27]CC)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH:8]=[CH:7]3)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: O=C(Cn1ccc2cc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)ccc21)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate and biphenyl-4-sulfonyl chloride following the procedures of Example 10 Step 4 & Step 5: MS (ESI) m/z 554; MS (ESI) m/z 552
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:12][CH3:13])=[C:5]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][N:23]=1)CCC>>[CH3:13][S:12][C:4]1[S:3][C:2]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)=[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CSc1sc(Br)c2c1C(=O)CCC2
Product: CSc1sc(-c2ncco2)c2c1C(=O)CCC2

Procedure:
In a similar way to that in Example 35, using 1-bromo-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 2-(tri-n-butylstannyl)oxazole, the title compound was isolated as a pale yellow solid (35 mg, 37%). mp 157-159° C. Found: C, 54.0; H, 3.7; N, 5.6%. C12H11NO2S2 requires: C, 54.32; H, 4.18; N, 5.28%. 1HNMR (250 MHz, CDCl3) δ 2.05-2.16 (2H, m), 2.56-2.61 (2H, m), 2.63 (3H, s), 3.20-3.25 (2H, m), 7.20 (1H, s), 7.66 (1H, s). MS (ES+) 266 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[H-].[Na+].Cl[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:33][C:30]1[CH:29]=[N:28][C:27]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[C:6]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[N:32][CH:31]=1
Reactant: CCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (135 mg) was dissolved in THF (15 ml) and sodium hydride (80 mg) was added followed by stirring for 15 min at 50° C. Then 2-chloro-5-bromo-pyrimidine (162 mg) was added and stirring was continued for 8 h at 70 C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethylacetate. The combined organic extracts were dried over magnesium sulfate and the solvent was evaporated. The crude material was purified by plate chromatography with ethyl acetate/hexane=½ to give ethanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (68 mg) as a white powder. LC-MS: tR: 4.64, [M+H]+: 496.19.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:5]1[CH2:6][C@@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([O:9][CH3:10])=[O:8])=[O:24]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1Br
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
Into a flame-dried 100 ml three-necked round-bottomed flask containing 30 ml of distilled THF was placed 3.00 g (16.575 mmol) of (cis)-4-hydroxy-L-proline, methyl ester; the vessel was immersed in an ice/water bath and the suspension was allowed to stir under argon for 5 minutes. At this time, 6.35 ml (36.465 mmol) of diisopropylethylamine was added slowly via syringe; the mixture was allowed to stir for 10 minutes, whereupon 3.64 g (16.576 mmol) of 2-bromobenzoyl chloride was added dropwise via syringe over the course of 10 minutes. The mixture was allowed to stir at 0° for 2 hours then gradually brought to room temperature overnight. The mixture was concentrated under vacuum to a minimal volume, transferred to a separatory funnel, and diluted with 100 ml of ethyl acetate, then washed with 1N HCl (2×30 ml), saturated sodium bicarbonate (2×30 ml), and brine (30 ml). The organic solution was dried over sodium sulfate, filtered, and concentrated under vacuum. Recrystallization from hot ethyl acetate yielded 3.034 g (55.6%) of the title compound, m.p. 145.5°-146.8° C.; a second recrystallization of the mother liquor yielded 1.726 g to bring the net yield to 4.760 g (87.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]([NH:24][C:25]3[N:29]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=3)=[O:23])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.ClC(Cl)(Cl)[C:43]([N:45]=C=O)=[O:44]>N1C=CC=CC=1>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[NH2:45])[CH:7]=3)=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(NC(N)=O)c3)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (7) (Intermediate D) (50 mg, 0.094 mmol) in pyridine (1.0 mL) was added trichloroacetylisocyanate (12 μl, 0.103 mmol). The mixture was stirred at RT until judged to be complete by LC-MS and solvent was evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and triturated from DCM (10 mL) to give 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-3-(pyridin-2-yl)urea (Example 21) as an off white solid (25 mg, 44%): m/z 578 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 H, s), 6.94-6.99 (2 H, m), 7.19 (1 H, dd), 7.33-7.35 (2 H, m), 7.41-7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].COC(C)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: BrP(Br)Br
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Clc1ccc(Br)cc1CBr
Temperature: 0 °C
Yield: 156.3 %

Procedure:
To a solution of 2.08 g (9.39 mol) of 5-bromo-2-chlorobenzylalcohol in 30 ml of dry diethyl ether was added dropwise 1.27 g (4.23 mmol) of phosphorous tribromide with ice-cooling. The mixture was stirred with ice-cooling for 3 hours and stirred at room temperature for 1.5 hours. To the reaction solution were added ice water and then tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated. The solid residue (1.99 g) was subjected to silica gel column chromatography (eluted with n-hexane) to obtain 1.88 g of 5-bromo-2-chlorobenzylbromide as flocculent crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)CC1

Procedure:
5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 1-Methyl-piperazine following General Procedure C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:31]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCCNCCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(CCC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-propylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 361 (M+, 0.2), 332 (6), 115 (9), 114 (bp), 86 (7), 72 (4).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][N:16]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:28].[CH2:29]([CH:32]1[O:34][CH:33]1[CH2:35]O)[CH2:30][CH3:31]>>[CH2:22]([O:21][C:18]1[CH:19]=[N:20][C:15]([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:28][CH2:35][CH:33]3[CH:32]([CH2:29][CH2:30][CH3:31])[O:34]3)[C:8]2([F:13])[F:14])=[N:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)nc1
Reactant: CCCC1OC1CO
Product: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3OCC3OC3CCC)C2(F)F)nc1

Procedure:
From 2,3,5,5-tetrafluoro-6-(5-hexyloxypyrimidin-2-yl)-5,6,7,8-tetrahydronaphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.