Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:33][C:34](Br)=[O:35].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:33][C:34]([NH:44][CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=1)=[O:35]
Reactant: NCc1ccccn1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c(OCc4ccccc4)ccc(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OCc4ccccc4)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5-benzyloxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([F:13])[CH:7]=1)(=O)C.C(O)C.O.S(=O)(=O)(O)O>CCOCC>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[CH:7][C:8]=1[F:13]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=Cc1ccc(Br)c(F)c1

Procedure:
A mixture of 4-bromo-3-fluorobenzylidene diacetate (15 g), ethanol (41 ml), water (41 ml) and concentrated sulphuric acid (4 ml) was heated to reflux for 3 hours. After cooling, ether (300 ml) was added and the aqueous layer separated. The organic phase was washed with saturated sodium carbonate and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. 4-Bromo-3-fluorobenzaldehyde was obtained as a solid (7.3 g).
Reaction SMILES: [OH-].[K+].O.CO.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)=[CH:24][CH:25]=3)[N:20](S(C3C(C)=CC(C)=CC=3C)(=O)=O)[N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)=[CH:24][CH:25]=3)[NH:20][N:19]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COCOc1ccc(-c2ccc3c(C=Cc4ccc(OC)c(OC)c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3c(/C=C/c4ccc(OC)c(OC)c4)n[nH]c3c2)cc1OC
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mL total) was prepared under argon and was degassed by vacuum/purge cycles with argon (5 times). In a separate flask, 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (289 mg, 0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon. To this solution was added the above 1M KOH solution (10 mL, 1:1 water/MeOH). The reaction was warmed to 30° C. and was allowed to stir for 7 h. The reaction mix was neutralized by the addition of 20% citric acid (7 mL). The resulting mix was partitioned between ethyl acetate (150 mL) and water (100 mL). The organic material was separated, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give cis and trans 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (used crude): Rf sm 0.46, p1 0.17, p2 0.23 (ethyl acetate-hexane 1:1); 1H NMR cis isomer (CDCl3) δ 7.55 (s, 1H), 7.3–7.1 (m, 6H), 7.02 (dd, 1H, J=1.9, 8.3 Hz), 6.85 (d, 1H, J=12.5 Hz), 6.78 (d, 1H, J=12.5 Hz), 6.74 (d, 1H, J=8.3 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 3.43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H]/z Calc'd 447. found 447. [m−H]/z Calc'd 445. found 445.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].C(NC(=O)[O-])C.[OH:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:23]([CH3:31])[CH:24]3[CH2:28][NH:27][CH2:26][CH:25]3[C:29]=2[CH:30]=1.C(Cl)[Cl:33]>CC#N.O>[CH:5]1([CH2:4][O:18][C:19]2[C:20]([Cl:33])=[CH:21][C:22]3[CH:23]([CH3:31])[CH:24]4[CH2:28][NH:27][CH2:26][CH:25]4[C:29]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: BrCC1CC1
Reactant: ClCCl
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1c2cc(Cl)c(OCC3CC3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(Bromomethyl)cyclopropane (13 mg, 0.09 mmol) and K2CO3 (24 mg, 0.17 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (23 mg, 0.09 mmol) in CH3CN, and stirred overnight at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H25NO3+H: 316, observed: 316.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10](N)=[O:11].S(=O)(=O)(O)O.[CH:18](O)=O>C1(C)C(C)=CC=CC=1.O>[C:1]1([N:7]2[CH:18]=[N:9][C:10]([OH:11])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: NC(N)=O
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Oc1ncn(-c2ccccc2)n1
Temperature: 135 °C

Procedure:
108 g (1 mol) of phenyl hydrazine and 60 g (1 mol) of urea were suspended in 500 ml of xylene and 111 g (1 mol) of concentrated sulfuric acid were added while stirring vigorously. The mixture was heated for 2.5 hours at 135° C. and water formed was separated via a water separator. After cooling to 90° C. 135.2 g (2.5 mols) of 85% formic acid and 25 g (0.25 mol) of concentrated sulfuric acid were added successively and the mixture was further heated for 6 hours at 95° C. After cooling, the product was filtered off, washed thoroughly with water until free from acid and dried in vacuo at 100° C. There were obtained 124.6 g (77.5% of the theory) of 1-phenyl-3-hydroxy-1,2,4-triazole having a melting point of 281°-282° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][NH:16][C:17](=[O:18])[C:10]3[C:11]4[C:12]2=C(NC=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1.[H-].[Na+].[CH3:22]I.[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][N:16]([CH3:22])[C:17](=[O:18])[C:10]3[C:11]4[C:12]2=[C:27]([N:25]([CH3:24])[C:26]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1N=C2CC(C)(C)Cc3c2c2c(cccc2n3C)C1=O
Yield: 95 %

Procedure:
The desired product was prepared using a procedure similar to step 1 of Example 22. Subsequently, 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (0.02 g, 0.08 mmol) was reacted with NaH (2.4 mg, 0.1 mmol) and methyl iodide (0.06 g, 0.4 mmol) in DMF (2 ml) to give the desired product (20 mg, 95%) as yellow solid. 1H NMR (DMSO-d6) δ 7.51-7.55 (m, 2H), 7.16 (t, 1H, J=7.8 Hz), 3.69 (s, 3H), 3.42 (s, 3H), 2.72 (s, 2H), 2.27 (s, 2H), and 1.09 (s, 6H). MS (ESI) m/e [M+1]+ 282.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:16]#[N:17])=[C:4]([I:14])[C:5]=1[O:11][CH2:12][CH3:13])(=[O:10])[CH3:9]
Reactant: [C-]#N
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Yield: 77.9 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.0 g, 2.9 mmol, from Example 211, Step 1) and potassium cyanide (0.29 g, 4.4 mmol) in DMF (11 mL) was stirred at 40° C. for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×75 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was dissolved in 1:1 hexane/dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.79 g, 77%). LCMS for C11H10ClINO2 (M+H)+: m/z=349.9. Found: 349.9.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:21]([N:3]1[C:4]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc2nc[nH]c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.12 g of methyl 3H-benzimidazole-4-carboxylate in 25 ml of dichloromethane is admixed with 0.97 ml of triethylamine and a solution of 2.010 g of trityl chloride in 25 ml of dichloromethane. The reaction mixture is stirred at room temperature over 16 hours and subsequently poured onto a 100 ml of semisaturated aqueous sodium hydrogencarbonate solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by flash chromatography (SiO2 60F). Rf (1:2 EtOAc-heptane)=0.25; Rt=4.31.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[NH2:19][NH2:20].[BH4-].[Na+].N>CO.C(Cl)Cl>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH:14]([NH:19][NH2:20])[CH2:13][CH2:12]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of 1-CBZ-4-piperidone (2.92 g, 12.5 mmol) and hydrazine hydrate (2.01 mL, 18.8 mmol) in MeOH (25 mL) was stirred at 50° C. for 30 min, then cooled to RT and NaBH4 (1.18 g, 31.3 mmol) added (CARE: gas evolution and exotherm to −45° C.). The solution was stirred at RT for 30 min, then 50° C. for 18 h. The cooled solution was concentrated in vacuo, suspended in water (25 mL) and extracted with DCM (2×25 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a clear oil. FCC, using 0-10% [2H NH3 in MeOH] in DCM, gave the title compound as a clear oil (1.80 g, 58%). LCMS (Method 3): Rt 2.03 min, m/z 250 [MH+].
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[NH:3][C:2]1=[O:16].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:20]3[CH:19]=[C:18]([N:13]4[CH2:12][CH2:11][C:4]5([C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[NH:1][C:2](=[O:16])[NH:3]5)[CH2:15][CH2:14]4)[N:23]=[CH:22][N:21]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=C1Nc2ccccc2C2(CCNCC2)N1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)NC(=O)Nc3ccccc34)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87.0 mg (0.400 mmol) 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one, 122 mg (0.400 mmol) 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.140 mL (0.800 mmol) DIPEA were combined in 3.0 mL DMF and stirred for 48 h at RT. The reaction mixture was diluted with MeOH, the precipitate was suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.CCOC(C(P(OCC)(OCC)=O)F)=O.[CH2:27]([N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH:42]([CH3:44])[CH3:43])=[CH:36][C:37]=2[C:39](=[O:41])[CH3:40])[C:32]([CH3:46])([CH3:45])[CH2:31][CH2:30]1)[CH3:28]>C1COCC1>[CH:42]([C:35]1[CH:34]=[C:33]2[C:38](=[C:37]([C:39](=[O:41])[CH3:40])[CH:36]=1)[N:29]([CH2:27][CH2:28][CH3:1])[CH2:30][CH2:31][C:32]2([CH3:45])[CH3:46])([CH3:43])[CH3:44]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Reactant: [Li]CCCC
Agent: CCOC(=O)C(F)P(=O)(OCC)OCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of a 1.6 M solution of n-butyl lithium in hexane (3.33 ml, 5.33 mmol) and 20 ml of anhydrous THF under argon at −78° C. was slowly added triethyl-2-fluoro-2-phosphonoacetate (1.29 g, 5.33 mmol). After 40 minutes at −78° C., a solution of 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethanone (Intermediate 12, 497 mg, 1.33 mmol) in 4 ml THF was added by cannula. The resulting mixture was stirred at −78° C. for 10 minutes, allowed to warm up to room temperature, and then heated to 80° C. for 12 hours. The reaction was quenched with saturated NH4Cl and product was extracted with ethyl ether. The extract was washed with water, and brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography using 2% ethyl acetate in hexane to yield the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:34]([CH:36]([CH2:39][CH3:40])[CH2:37][NH2:38])[CH3:35]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH2:37][CH:36]([CH2:39][CH3:40])[CH2:34][CH3:35])=[O:23])(=[O:15])=[O:16])[CH2:12]2)=[CH:28][CH:29]=1
Reactant: CCC(CC)CN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CCC(CC)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 42.7 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 19 mg of 2-ethylbutylamine. 47 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide are thus obtained in the form of a pale yellow powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.86 (t, J=7 Hz, 6H), from 1.20 to 1.40 (mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.42 (t, J=6 Hz, 1H)].
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=1)=[C:9]([C:30]1[S:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH:8]=[CH:7]2.B(Br)(Br)Br.Cl>ClCCl.CO>[CH3:35][C:32]1[S:31][C:30]([C:9]2[C:10]([O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12]3)=[CH:34][CH:33]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C)s3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
Dissolve 1-(2-(4-(6-methoxy-2-(5-methylthiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine hydrochloride (5.15 g, 10.1 mmol) in dichloromethane (340 mL). Cool the resulting solution to 0° C. In a separate container under nitrogen combine neat boron tribromide (3.9 mL, 40.4 mmol) and dichloromethane (36.5 mL). Add the resulting boron tribromide solution to the cooled solution. Stir the resulting mixture at 0° C. for 2.5 hours. Quench the mixture with saturated aqueous sodium bicarbonate and allow it to warm to room temperature. Separate the layers and extract the aqueous layer with 20% methanol in dichloromethane (10 mL×3). Concentrate the combined organic solutions to give a solid. Slurry the solid in methanol (234 mL) and add HCl (1N in water; 10.8 mL). Load the resulting solution onto an SCX acidic ion exchange column. Flush the column with 40% methanol in dichloromethane then elute desired material with 40% 7M ammonia in methanol in dichloromethane. Concentrate the ammonia containing eluent to give the title compound (4.54 g, 9.88 mmol). LRMS (m/z): 460 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:30][C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2ccc(OCc3ccc(C(F)(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 4-trifluoromethylbenzyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 21% yield: mp 278-280° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.65-8.62 (m, 1H), 7.78-7.64 (m, 4H), 7.30-7.29 (m, 5H), 6.44-6.41 (m, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.30 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.3, 161.9, 161.6, 153.9, 150.4, 140.7, 139.9, 132.3, 128.8, 128.7, 127.7, 127.2, 126.4, 126.0, 125.9, 123.8, 104.3, 97.7, 69.8, 43.1, 17.5; MS (ES+) m/z 500.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41]O)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C.Cl.[F:72][CH:73]1[CH2:76][NH:75][CH2:74]1>C(Cl)Cl.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41][N:75]4[CH2:76][CH:73]([F:72])[CH2:74]4)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)C4)cc12
Reactant: FC1CNC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN3CC(F)C3)C4)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
To a solution of 5-(11-fluoro-6-(hydroxymethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, 0.280 mmol) in DCM (8 mL) at 0° C. was added trifluoromethanesulfonic anhydride in DCM (0.560 mL, 0.560 mmol). The mixture was stirred at 0° C. for 2 h, then at RT for 1 h. The mixture was evaporated in vacuo to remove the volatiles, redissolved in DMF (8 mL), followed by addition of N,N-diisopropyl ethylamine (362 mg, 2.80 mmol) and 3-fluoroazetidine hydrochloride (125 mg, 1.120 mmol). The mixture was heated to 60° C. and stirred for 3 h. 20 ml H2O was added and the mixture stirred for 10 min. Filtration collected the yellow solid. After washing with additional H2O, the yellow solid was purified by chromatography, and eluted with 0-70% ethyl acetate in hexane to gave 5-(11-fluoro-6-((3-fluoroazetidin-1-yl)methyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (42 mg, yield: 21%). MS (M+H)+: 700.
Reaction SMILES: [NH2:1][C:2]1([C:35](OC)=[O:36])[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:32](=[CH:33][CH:34]=2)[C:13]2=[N:14][O:15][C:16]([C:17]4[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:19][N:18]=4)=[C:12]2[CH2:11][CH2:10]3)[CH2:3]1.CCO.[BH4-].[Na+].[OH-].[Na+]>O.ClCCl>[NH2:1][C:2]1([CH2:35][OH:36])[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:32](=[CH:33][CH:34]=2)[C:13]2=[N:14][O:15][C:16]([C:17]4[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:19][N:18]=4)=[C:12]2[CH2:11][CH2:10]3)[CH2:3]1
Reactant: COC(=O)C1(N)CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: NC1(CO)CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Methyl 1-amino-3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentanecarboxylate (Preparation 121F, 160 mg, 0.306 mmol) was mixed with EtOH (2 mL), dichloromethane (1 mL) and sodium borohydride (57.8 mg, 1.528 mmol). The mixture was stirred at room temperature overnight. Next, 2N aqueous sodium hydroxide solution (5 mL) was added. The mixture was stirred at 40° C. for 30 min. and cooled. Water (10 mL) was added. The mixture was extracted with EtOAc (10 mL, 2×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure to give a (1-amino-3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentyl)methanol (151 mg, 0.305 mmol, 100% yield) as a foam solid.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:5])=[S:4].[CH2:6]([Br:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.CCOCC>[BrH:13].[CH2:6]([S:4][C:3](=[NH:5])[CH2:2][F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=S)CF
Reactant: BrCc1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Br
Product: N=C(CF)SCc1ccccc1
Yield: 54 %

Procedure:
Fluorothioacetamide (3.39 g) and benzyl bromide (6.23 g) were refluxed in chloroform (40 ml), under nitrogen, for 16 h. After colling, the mixture was diluted with ether (200 ml) and the resulting orange solid filtered off. The solid was washed with more ether and dried over P2O5 in vacuo to give 5.19 g of the desired product.
Reaction SMILES: Cl[Pd:2]Cl.[OH:4][S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6]>C(Cl)Cl>[O-:7][S:5]([C:8]([F:11])([F:10])[F:9])(=[O:6])=[O:4].[Pd+2:2].[O-:7][S:5]([C:8]([F:11])([F:10])[F:9])(=[O:6])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Cl[Pd]Cl
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: [Pd+2]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PdCl2 (1.0 g, 5.6 mmol) was slurried in CH2Cl2 (20 mL) and triflic acid (1.7 g, 11.3 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The solvent was removed and 0.9 g of rust color solid was collected. 19F NMR (CDCl3): δ-78.5.