Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+].O>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
3-Quinolinecarbaldehyde (Aldrich) (1.04 g, 6.64 mmol) was dissolved in anhydrous ethanol (20 mL), NaBH4 (0.250 g, 3.95 mmol) was then added in small portions over 10 min and the resulting solution allowed to stir for a further 30 min. Water (20 mL) was then added and the resulting solution extracted with ethyl acetate (2×30 mL). The combined organics were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the sub-title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:34][CH2:35]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see below) and amine 5.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:15])=[O:30])=[CH:12][CH:13]=2)[O:6][C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Temperature: -22.5 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
To a solution of 23 (334.31 g, 1.11 mol) in anhydrous dichloromethane (5.46 L) at −30° C., mCPBA (255.29 g, 1.11 mol) in anhydrous dichloromethane (3.45 L) was added drop-wise over 2 hours. The reaction mixture was stirred at −20 to −25° C. for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with saturated NaHCO3 (5.8 L) at −20° C. The organic layer was separated, washed with water (3×2 L), brine (2 L), dried over Na2SO4and concentrated to provide 358 g of crude desired product. 1H NMR (400 MHz, CD3OD) 2.80 (s, 3 H), 4.34-4.43 (m, 1H), 4.48-4.52 (m, 1H), 4.65-4.70 (m, 2H), 4.72-4.80 (m, 2H), 5.79 (d, J=8 Hz, 1 H), 7.45-7.48 (m, 2 H), 7.58-7.62 (m, 3H), 7.76-7.89 (m, 2H), 8.02-8.10 (m, 2H). The crude material was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:28]I>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: COc1ccc(CC(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(C)C(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1

Procedure:
In analogy to Example 1, step 2, 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an off-white oil. MS (m/e, ISP neg. ion)=376.2 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Reactant: CN1CCNCC1
Product: CN1CCN(C2Cc3cc(Cl)ccc3Sc3cc(F)ccc32)CC1

Procedure:
12 g of 2,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are heated for 10 minutes together with 16 g of N-methylpiperazine at an external temperature of 120°-130°. After cooling the reaction mixture is poured on water and extracted with ether. The organic phase is washed with water and subsequently treated with 2 N hydrochloric acid. A precipitate is obtained. The mixture is extracted with ether, made alkaline and subsequently again extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The so-obtained raw 1-(2-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-4-methylpiperazine is converted to the corresponding maleate by treatment with maleic acid. The maleat melts at 200° with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:11][C:12]#[C:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.[OH-:26].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:11][CH:12]([C:13](=[O:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(S(=O)CC#CCOc2ccccc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C(=O)COc1ccccc1)CS2
Reaction time: 18 h

Procedure:
NMR analysis of both gums indicated the second to be of higher purity, so this was used in the subsequent stages. A mixture of the crude 1-(4-methoxyphenylsulphinyl)-4-phenoxybut-2-yne (2.1 g) and chloroform (25 ml) was heated under nitrogen at an external temperature of 80°-85° C. for 1 hour, allowed to stand at ambient temperature for 18 hours, and heated at an external temperature of 90°-95° C. for 6 hours. The solvent was removed by distillation to leave crude 5-methoxy-3-methylene-2-phenoxymethyl-2,3-dihydrobenzo[b]thiophen-2-ol as an orange gum. The orange gum was dissolved in dichloromethane (30 ml) and the solution was shaken vigorously for a few seconds with 5M aqueous sodium hydroxide solution (25 ml), then the organic solution was separated, washed with water (25 ml), dried (MgSO4), and the solvent removed in vacuo to leave crude 1-(5-methoxy-2,3-dihydrobenzo[b]thiophen-3-yl)-2-phenoxyethanone as a red gum (1.94 g) which was used without purification.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Br:27][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one (1.50 g, 4.41 mmol) in N,N-dimethylformamide (15 mL), carbon tetrabromide (1.60 g, 4.85 mmol), and triphenylphosphine (1.30 g, 4.85 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the product was purified by the Simpliflash system, using 1-2% methanol in CH2Cl2 as eluent, to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 1.77 g (quantitative).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-])=O.[NH2:15][C@@H:16]([C:20]([NH2:22])=[O:21])[CH:17]([CH3:19])[CH3:18].Cl.CO.C(N(CC)CC)C>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([C@H:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH2:22])=[O:21])[C:9]2=[O:14]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (2 g, 0.01 mol) and H-D-Val-NH2HCl (1.9 g, 0.012 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-30% EtOAc/Hexane) to give a yellow solid. MS m/z 290.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CO>[N:13]([CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of the commercially available 4-bromoacetyl-benzonitrile (5 g, 22.32 mmol) in 150 mL of methanol was added sodium azide (1.74 g, 26.78 mmol) and the contents stirred at room temperature for 2 h. After removal of the solvent, the residue was treated with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated to give a yellow solid (3.90 g, 94%). This compound was used for the next step without any further purification.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Br:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C(O)C>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[O:34])[CH2:26][C:25]([C:11]1[CH:12]=[C:13]([Br:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:27])[CH3:33]
Reactant: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
9.75 g sodium (0.424 mol, 3 eq) were dissolved in 500 ml absolute ethanol (1.5 hours). 58 g of 1-(2,4-Bis-benzyloxy-5-bromo-phenyl)-ethanone (0.141 mol, 1 eq) and 30.98 g diethyl oxalate (0.212 mol, 1.5 eq) were added and the mixture was refluxed for 2 hours. After cooling down, the mixture was poured onto 220 ml of 2N aqueous HCl and the product was extracted into 700 ml dichloromethane. The solvent was removed under reduced pressure and the yellow residue was triturated with 150 ml diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1
Yield: 89.5 %

Procedure:
A mixture of 4-chlorophenol (2.00 g, 15.56 mmol), 2-fluorobenzonitrile (1.88 g, 15.56 mmol) and potassium carbonate (2.15 g, 15.56 mmol) in DMF (10 mL) was stirred under reflux for 4 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 2-(4-chlorophenoxy)benzonitrile (3.2 g, 90%) as a white solid, mp 84-86° C., which was used in the next step without further purification. Rf: 0.62 (DCM) 1H NMR (270 MHz, CDCl3) δ 6.86 (1H, dd, J=8.4, 0.8 Hz), 7.02 (2H, AA′BB′), 7.15 (1H, td, J=7.7, 1.0 Hz), 7.35 (2H, AA′BB′), 7.48 (1H, m) and 7.65 (1H, dd, J=7.7, 1.5 Hz). LC/MS (APCI) tr=4.66 min, m/z 232.28 (31), 230.27 (M++H, 100).
Reaction SMILES: [CH:1]1([C@H:7]([NH:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:1]1([C@H:7]([N:11]([C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)[NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=CC[C@H](C1CCCCC1)N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of (R)-3-methoxy-2-methyl-benzoic acid N′-(1-cyclohexyl-but-3-enyl)-hydrazide (1.3 g, 4.11 mmol) in CH2Cl2 (5 mL), was added K2CO3 (2.27 g, 16.44 mmol), H2O (5 mL), and finally 3,5-dimethylbenzoyl chloride (727 mg, 4.31 mmol). The reaction was stirred at room temperature for 24 h. Additional CH2Cl2 and H2O were added to aid manipulation, the CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The CH2Cl2 solutions were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to provide (R)-3,5-dimethyl-benzoic acid N-(1-cyclohexyl-but-3-enyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide as a white solid (1.45 g, 78% yield). Rf=0.21 (3:1 EtOAc:n-Hexane); 1H NMR (400 MHz, DMSO-d6) δ 10.47+10.39 (2 s, 1H), 7.20-7.01 (m, 5H), 6.37 (d, J=7.2 Hz, 1H), 6.22-5.89 (m, 1H), 5.18 (dd, 1H), 5.02 (dd, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 2.44-2.34 (m, 2H), 2.29 (s, 3H), 2.02-1.53 (m, 8H), 1.26-1.02 (m, 3H); HRMS (ESI) m/z calcd for C28H37N2O3 [M+H]+ 449.2804, found 449.2793, calcd for C28H36N2NaO3 [M+Na]+ 471.2624, found 471.2615.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([S:35]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])(=[O:37])=[O:36])[N:30]=[CH:29]4)[C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.[N:53]1([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:53]1([CH:59]2[CH2:64][CH2:63][N:62]([C:22](=[O:23])[C@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([S:35]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])(=[O:36])=[O:37])[N:30]=[CH:29]4)[CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a solution of (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid (554 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4-piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP® (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94:5:1) as eluent to give 599 mg (87%) of the title compound as a white solid. 1H-NMR (CD3CN, 300 MHz) δ 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (m, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H), 7.55-7.46 (m, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (m, 1H), 6.79 (d, J=8.1 Hz, 1H), 5.71 (t, J=8.1 Hz, 1H), 5.00 (dd, J=15.0, 8.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (m, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (m, 2H), −0.04 (s, 9H). Mass spec.: 778 (MH)+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1.O>C(Cl)(Cl)Cl>[N:5]([C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[C:1]=[S:2]
Reactant: Cc1cc(N)cnc1C#N
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(N=C=S)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Thiophosgene (0.24 mL, 3.1 mmol) was added to a stirred biphasic solution of 5-amino-3-methylpicolinonitrile (Intermediate 2, 275 mg, 2.07 mmol) in CHCl3 (6 mL)/water (10 mL) and the resulting orange mixture was stirred at room temperature overnight. The two layers were separated and the aqueous layer was extracted with DCM (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 300 mg of 5-isothiocyanato-3-methylpicolinonitrile as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.06 (s, 1H), 2.5 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:13]([NH:17][S:30]([CH:27]3[CH2:29][CH2:28]3)(=[O:32])=[O:31])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(N)ccc21
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 5-amino-4-(2-fluoro-4-iodo-phenylamino)-indazole-1-carboxylic acid tert-butyl ester (200 mg, 0.43 mmol) in pyridine (2 mL) was added cyclopropyl sulfonyl chloride (0.218 mL, 2.14 mmol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 10-35% ethyl acetate in cyclohexane) to yield the title compound (206 mg, 84%). LCMS (Method B): RT=4.17 min, [MH]+=573.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH2:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH:29][C:11]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]4[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=4)[O:10][N:9]=3)=[O:13])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(F)ccc12)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-fluoro-1H-indol-3-yl)ethanamine (0.051 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.040 g (41%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.C([O-])(O)=O.[Na+].[Cl:19][CH2:20]S(OCl)(=O)=O>O>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([CH2:20][Cl:19])=[O:6]
Reactant: O=S(=O)(CCl)OCl
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)CCl
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of IClSO3H (5 g, 42.91 mmol) and ClCH2Br (5.55 g, 42.9 mmol) was refluxed for 3 hours, followed by pouring into ice. The ice water suspension was extracted with DCM (2×50 mL), and the combined DCM layers were washed with water (2×50 mL) to give a solution of ClCH2SO3Cl (solution A). A solution of Boc-β-Ala-OH (12, 4.73 g, 25 mmol), NaHCO3 (8.41 g, 100 mmol), and Bu4N+HSO4− (0.849 g, 2.5 mmol) in water (100 mL) was cooled to 0° C., followed by addition of solution A. The mixture was stirred vigorously for 2 hours, followed by separation of the layers. The DCM layer was washed with brine (2×100 mL), and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (20% EtOAc in hexane, v/v) to yield 1.2 g (20%) of product (13): 13C NMR δ 28.218 (3×CH3 of Boc), 34.439 (CH2C(═O)O), 35.655 (NHCH2CH2), 68.565 (OCH2Cl), 79.547 (C(CH3)3), 155.811 (NHC(═O)O), 170.761 (C(═O)O).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH2:14]>P(=O)(O)(O)O.[Cl-].[Na+].O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[Br:12]
Reactant: O
Reactant: Nc1cc(Br)c2ncc(Br)cc2c1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: Oc1cc(Br)c2ncc(Br)cc2c1
Temperature: 180 °C

Procedure:
6-Amino-3,8-dibromoquinoline (1.1 g) was suspended in phosphoric acid (10 ml) containing water (10 ml) and heated in a sealed glass tube at 180° C. for 4 days. The mixture was cooled to ambient temperature, poured into brine and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate, evaporated under reduced pressure and the residual solid fractionated by chromatography (silica; hexane/ethyl acetate) to give 3,8-dibromo-6-hydroxy-quinoline, 0.4 g, as a pale brown solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][C:19](O)=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:9]([O:13][C:14](=[O:15])[NH:16][CH2:17][CH2:18][C:19](=[O:20])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Nc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.7 %

Procedure:
A mixture of 4-iodoaniline (2.0 g, 9.17 mmol), 3-tert-butoxycarbonylaminopropionic acid (1.61 g, 8.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.95 g, 10.19 mmol), 1-hydroxy-7-azabenzotriazole (0.12 g, 0.85 mmol), and DMF (20 mL), was stirred at room temperature for 72 hours. The solvent was evaporated in vacuo. The residue was dissolved in methylene chloride (100 mL) and washed with 10% citric acid (2×50 mL), then 10% aqueous K2CO3 (2×50 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1, v/v hexanes/ethyl acetate, then 1:1 hexanes/ethyl acetate) to provide 310 (2.44 g, 69%). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 2.60 (t, 2H), 3.49 (q, 2H), 7.36 (d, 2H), 7.60 (d, 2H).