Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=1>CN(C)C=O>[CH3:37][O:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(CCl)n1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 85.9 %

Procedure:
Tetrahydrofuran (3 mL) and a 5N sodium hydroxide aqueous solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-6-methoxy-pyridine (21.2 mg, 0.13 mmol) described in Manufacturing Example 99-1-2, which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and this residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36.7 mg, 84%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:38]=1>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:39]=1[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH3:45]
Reactant: CCOc1ccc(CBr)cc1OCCCOC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
Analogously to Method D, 0.496 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.502 g of 4-bromomethyl-1-ethoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.26 (1:2 EtOAc-heptane); Rt=6.20.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@:4]12[O:29][C@:7]3([C@@H:15]4[C@@H:11]([N:12]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=5)[C:13](=[O:16])[C@H:14]14)[O:10][CH2:9][CH2:8]3)[C:6](=[O:30])[CH2:5]2>C1COCC1.CO>[OH:30][C@@H:6]1[CH2:5][C@@:4]2([CH3:3])[O:29][C@@:7]31[C@@H:15]1[C@@H:11]([N:12]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=4)[C:13](=[O:16])[C@H:14]21)[O:10][CH2:9][CH2:8]3
Reactant: C[C@@]12CC(=O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@]12C[C@@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
Sodium borohydride (0.56 g, 14.7 mmol) was added in portions to a solution of Example 5 (2.9 g, 7.39 mmol) in THF (10 mL) and MeOH (10 mL) at 0° C. The reaction mixture was stirred for 15 min and quenched with drop-wise addition of aqueous saturated ammonium chloride (20 mL). The organic solvents were removed in vacuo and the residue was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography using an 80 g ISCO column eluting with 0-100% EtOAc in CH2Cl2 at 70 mL/min. Concentration of appropriate fractions provided 2.9 g (99%) of Example 6 as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:3][C:4]=1[N:13]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=1)[S:14]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(Br)c3ccccc3c2C)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(N3CCCC3)c3ccccc3c2C)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 24.3 %

Procedure:
A mixture of ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (93.5 mg, 0.15 mmol) prepared in Example 9-(1), pyrrolidine (0.015 mL, 0.18 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.3 mg, 0.015 mmol), trisdibenzylideneacetone dipalladium (6.9 mg, 0.0075 mmol) and sodium-t-butoxide (20.2 mg, 0.21 mmol) in toluene (2 mL) was stirred at 100° C. for 4 hours under argon atmosphere. The mixture was cooled to room temperature, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10%→25%) to give ethyl 4-({(4-methyl-1-pyrrolidin-1-ylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (22.4 mg, 24%) as a yellow viscous material.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](O)=[N:16][CH:17]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:1][CH:2]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)=[N:16][CH:17]=1
Reactant: Oc1ccc(Br)cn1
Reactant: COC(=O)C1CCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(Oc2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
A solution of methyl 3-hydroxycyclopentanecarboxylate A-11 (500.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) was added to a solution of 5-bromopyridin-2-ol (522.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) at room temperature. Diisopropyl azodicarboxylate (1.57 g, 6.00 mmol) was then added dropwise, and the yellow-orange solution was stirred at room temperature for 12 h. The reaction mixture was then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)cyclopentane carboxylate A-12 (462.0 mg, Yield=51%). MS (ESI), [M+Na]+ 321, 323.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:33][C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]3)=[CH:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCN1CCOCC1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCN4CCOCC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.5 mmol) of 1-(2-morpholin-4-yl-ethyl)-3-piperidin-4-yl-1H-indole and 1.8 g (7.8 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up and purification, 0.75 g (22% of yield) of the expected acid were obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[F:13][C:14]([F:23])([F:24])[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]2)=[CH:21][CH:22]=1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 113 %

Procedure:
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (2.0 g, 12 mmol) and 4-(trifluoromethoxy)aniline (1.34 mL, 10.0 mmol) gave (R)-3-[4-(4-trifluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a pale yellow solid (3.7 g, 94%).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:23])(=[N:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[O:15])=[CH:10][CH:9]=2)[O:6]C(C)(C)[N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:4][C@H:3]([CH2:2][F:1])[C@@H:7]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:23])(=[N:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[O:15])=[CH:12][CH:13]=1)[OH:6]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)oxazolidine-3-carboxylate (500 mg, 1.168 mmol) in DCM (20 mL) is added Trifluoroacetic acid (2.0 mL). Reaction mixture is allowed to stir at room temperature for 2 h. Excess of Trifluoroacetic acid and DCM is evaporated in vacuo, stripped with toluene followed by washing with n-pentane and diethyl ether to afford crude title compound (426 mg, TFA salt) as faint yellow sticky mass which is used as such for next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]([CH:11]=[C:7]([CH2:8][OH:9])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (8.66 g, 0.0293 mol) in THF (60 mL) was slowly added borane-dimethyl sulfide complex (7.8 mL, 0.088 mol) over 20 min at rt. The reaction mixture was heated at 50° C. for 2 h. An additional amount of borane-dimethyl sulfide complex (7.8 mL, 0.088 mol) was added to reaction mixture and the heat increased to 80° C. The reaction mixture was allowed to stir for an additional 2 h. Unreacted borane was quenched by the addition of MeOH. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography and triturated to give methyl 3-tert-butyl-5-(hydroxymethyl)benzoate (3.0 g, 46%) as a white solid. LCMS ES+ 223.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH2:18][OH:19])=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl.C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH:18]=[O:19])=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Manganese (IV) oxide (4.7 g, 54 mmol) was added to a mixture of [5-(3-pyrrolidin-1-yl-propyl)-1H-indol-2-yl]-methanol (940 mg, 3.6 mmol) in dichloromethane (150 mL) and toluene (150 mL). The mixture was stirred at room temperature for overnight. The reaction was filtered through a pad of celite and the filtrate was concentrated to give 670 mg (72%) of 5-(3-pyrrolidin-1-yl-propyl)-1H-indole-2-carbaldehyde.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([OH:18])C2C(=CC=CC=2)C=CC=1.C>[I-].C([N+](CC)(CC)CC)C.[Rh]>[CH:1]1([N:7]=[C:8]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Oc1cccc2ccccc12
Agent: [Rh]
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Product: O=C=NC1CCCCC1

Procedure:
The carbonylation reaction is conducted in the same manner as in Example 1 except that 25 mmol of cyclohexylamine, 86 g of α-naphthol, 1.5 g of Rh/C having 5% Rh carried on activated charcoal and 1 mmol of tetraethylammonium iodide are employed. As a result, the yields of cyclohexyl isocyanate and α-naphthyl cyclohexyl carbamate are 58% and 10%, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)cc(C2OCCO2)c1
Yield: 99.8 %

Procedure:
A suspension of 3,5-dibromo-benzaldehyde (20.0 g, 75.8 mmol, 1.0 equiv; [CAS RN 56990-02-4]), ethane-1,2-diol (12.7 mL, 14.1 g, 227.3 mmol, 3.0 equiv) and p-toluene sulfonic acid monohydrate (0.29 g, 1.52 mmol, 0.02 equiv) in toluene (50 mL) was heated to reflux under Dean-Stark conditions for 1 h. The reaction mixture was extracted with ethyl acetate (3×200 mL), the combined organic phases washed with a sat. solution of sodium carbonate (4×50 mL) and dried over MgSO4. Removal of the solvent by evaporation under reduced pressure yielded 23.3 g (100%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.00-4.12 (m, 4H), 5.76 (s, 1H), 7.55-7.56 (m, 2H), 7.65-7.66 (m, 1H). MS (EI): 306.8 [M]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>O1CCOCC1>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspention of NaH (2.2 mmol, 55-65% in oil) in dry dioxane (6 mL) was added 2-methoxyethanol (158 μl, 2 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-methylphenyl)benzenesulfonamide (265.3 mg, 1 mmol) in dry dioxane (2 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (5 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×5 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. 4-(2-methoxyethoxy)-N-(4-methylphenyl)benzenesulfonamide was obtained as a colorless oil, in 77% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([I:25])=[CH:27][CH:28]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid (4.58 g, 14 mmol) in 100 ml toluene was added 4-iodoaniline (3.37 g, 15.4 mmol), N,N′-dicyclohexyl-carbodiimide (3.2 g, 15.4 mmol), and 4-dimethylaminopyridine (171 mg, 1.4 mmol). The reaction mixture was stirred at 100° C. for 16 h, and was filtered. The filtrate was concentrated and chromatography of the residue (10% ethyl acetate in hexane) afforded 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide as a grey powder (3 g, 41%). 1H NMR (CDCl3) δ 8.06-8.09 (2H, d, J=8.8 Hz), 7.56-7.59 (2H, d, J=8.5 Hz), 7.36-7.39 (2H, d, J=8.2 Hz), 7.27-7.30 (2H, m), 7.17-7.26 (4H, m), 6.95 (1H, s), 3.67-3.75 (2H, m), 3.08-3.17 (1H, m), 1.32 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[I:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[C:19]([I:28])=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)cc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(I)c2n1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a 0° C. stirred solution of cyclopentyl-[2-(2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino)-ethyl]-carbamic acid tert-butyl ester (89 mg, 0.24 mmol) in chloroform (5 mL) was added N-iodosuccinimide (54 mg, 0.24 mmol). After stirring 30 minutes the reaction was extracted from saturated aqueous sodium thiosulfate with chloroform. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the product as a slightly yellowed glass (102 mg, 85%): +APcI MS (M+1)+ 500; 1H NMR (CDCl3) δ: 5.82 (s, 1H), 4.25-4.10 (br s, 1H), 3.46 (s, 4H), 2.51 (s, 3H), 2.41 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:23]2[C:22]3[C:27](=[CH:28][C:19]([Br:18])=[CH:20][CH:21]=3)[N:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:12][CH:11]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)cc1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
1-(N-BOC-aminomethyl)-4-(aminomethyl)benzene (5.0 g, 21 mmol) in dichloromethane (50 mL) was added dropwise to a mixture of 7-bromo-4-chloro-3-nitroquinoline (5.81 g, 20 mmol) and triethylamine (5.63 mL) in dichloromethane (60 mL). The reaction was stirred for 16 hours and then washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over sodium sulfate, filtered and concentrated to provide a yellow crystalline solid. Recrystallization from 2-propanol yielded 9.1 g of tert-butyl{4-[(7-bromo-3-nitroquinolin-4-ylamino)methyl]benzyl}carbamate as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Br)ncc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ncc1F
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:25][N:26]([CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17]
Reactant: CNCCCN1CCCCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)CCCN4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Methyl-(3-piperidin-1-yl-propyl)-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid methyl-(3-piperidin-1-yl-propyl)-amide. LC-MS: m/e 465 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.[NH2:15][NH2:16]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:2])[NH:15][NH:16]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Product: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12

Procedure:
The crude material, 2-fluoro-4-nitro-benzoic acid methyl ester, from above was treated with hydrazine (1.6 mL, 51 mmol) in ethanol under reflux for 14 hrs. After removal of solvent by evaporation, the residue was washed with water. The precipitate product was filtered and dried on the vacuum pump to give the title compound which was used without further purification(4.0 g, 85% for two steps). MS (ES+): m/e=180.1 (M+H), 178.0 (M−H); LC/Method A/1.83 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: O=C(CCl)Nc1ccc(F)cc1F
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,4-difluorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 37.3 mg (74.8%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.52 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.08 (t, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.92 (m, 1H), 8.12 (d, J=5 Hz, 1H), 9.60 (s, 1H); MS (ESI/APCI+) m/e 333 (M+H)+.