Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[N+:28]([C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 60 °C
Yield: 77.9 %

Procedure:
A 20 mL round bottom flask was charged with (S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 0.25 g, 1.77 mmol), 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 37, 0.3 g, 1.0 mmol), and DIEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (5 mL) was added, and the flask was heated at 60° C. for 4 hours. The reaction mixture was washed with brine (5 mL×3), and the organic layer was dried and concentrated. The resulting residue was separated by silica gel column to afford desired product (0.3 g, 75%). LC-MS, 386 (M+1). 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 10.5 (s, 1H), 9.1 (s, 1H), 9.0 (s, 1H), 8.80 (s, 2H), 6.1 (s, 1H), 5.2 (dd, 1H), 2.0 (m, 1H), 1.7 (d, 3H), 1.0 (m, 2H), 0.8 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:21](=[O:22])[C:17]2[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][N:18]=2)=[N:2]1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCCNc1nsc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (100 mg, 0.52 mmol), 4-chloropicolinic acid (90 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.57 mmol) and triethylamine (174 μL, 1.1 mmol) in dichloromethane (5 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 1% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to give N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chloropicolinamide (50 mg) as a white solid. 1H NMR (300 MHz, CDCl3): 8.66 (broad s, 1H), 8.41 (d, 1H), 8.20 (s, 1H), 7.78 (t, 2H), 7.65-7.38 (m, 3H), 5.95 (broad s, 1H), 3.84 ppm (m, 4H). MW=333 confirmed by LC-MS, tr=12.38 min (Method Y) MH+=334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:24]([N:23]([CH3:22])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CNCC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added N-methylisobutylamine (0.15 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (108 mg, 44% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H31Cl N2 O2, 378.9, found, 379.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, δ 7.47-7.45 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.30 (m, 1H), 3.71 (s, 2H), 3.20-3.02 (m, 3H), 2.92 & 2.90 (2 s, 3H total), 2.80-2.70 (m, 2H), 2.60-2.50 (m, 6H), 1.95-1.80 (m, 1H), 1.78-1.70 (m, 4H), 0.76-0.58 (m, 6H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, line list δ 176.6, 175.8, 146.4, 135.2, 135.1, 134.0, 130.9, 130.8, 126.4, 123.7, 123.6, 73.5, 73.3, 57.9, 56.7, 55.6, 54.3, 41.4, 41.0, 36.1, 35.0, 29.0, 28.2, 27.9, 26.9, 23.7, 20.2, 20.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C[O-].[Na+].Br[CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C.C(O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:15]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
A solution of the product of step (a) (130 g) in dry DMF (400 ml) was added dropwise to a solution of sodium methoxide (56.2 g) in ethanol (400 ml) mechanically stirred under nitrogen. After a further 20 mins, a solution of 2-(bromomethyl)benzonitrile (182.2 g) in dry DMF (400 ml) was added dropwise. The mixture was then heated to 75° C. for 30min. The solution was allowed to cool for 1 h. A slurry of sodium methoxide (56.2 g) in dry DMF (100 ml) was added and the mixture heated at reflux for 1.5 h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 7) as a beige solid (149.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].C1COCC1>O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
To a 100-mL round-bottomed flask was added 3-methoxybenzyl bromide (0.73 mL, 5.22 mmol, Sigma-Aldrich, St. Louis, Mo.), ethyl N-(diphenylmethylene)glycinate (1.40 g, 5.22 mmol, Acros, Pittsburgh, Pa.), 5 M sodium hydroxide (5.22 mL, 26.1 mmol) and THF (20 mL). The reaction mixture was stirred at room temperature for 2 d. After that time, the mixture was diluted with water (30 mL) and extracted with EtOAc (2×60 mL). The organic extracts were washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. Purification by silica gel chromatography, eluting with 20% EtOAc in hexanes gave ethyl N-(diphenylmethylidene)-3-methoxyphenylalaninate (1.56 g).
Reaction SMILES: CC1(C)C2([CH2:10][S:11](O)(=[O:13])=[O:12])C(CC1CC2)=O.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[NH:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1.CN1CCOCC1.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[N:29]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Agent: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A mixture of 660 g of the d-10-camphorsulfonic acid salt of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one (IA) in 8 litres of methylene chloride and 404 g of N-methylmorpholine was cooled in an ice bath to 10° C. and 153 ml of methanesulfonyl chloride was added over 30 minutes, allowing the temperature to rise to 16° C. The mixture was stirred at 10°-16° C. for 90 minutes, then washed sequentially with water, IN hydrochloric acid, and water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residue was crystallized from methanol to give (8aS,12aS,13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 138°-140° C.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: FC1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [NH2:1][NH2:2].[NH2:3][C:4]1[C:16]([Br:17])=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=O)=[CH:6][C:5]=1[Br:18]>C(O)C>[NH2:3][C:4]1[C:16]([Br:17])=[CH:15][C:7]([C:8]2[CH2:10][CH2:11][C:12](=[O:13])[NH:1][N:2]=2)=[CH:6][C:5]=1[Br:18]
Reactant: Nc1c(Br)cc(C(=O)CCC(=O)O)cc1Br
Reactant: NN
Solvent: CCO
Product: Nc1c(Br)cc(C2=NNC(=O)CC2)cc1Br

Procedure:
The title compound was prepared as described in Example 1 starting with hydrazine and 3-(4-amino-3,5-dibromobenzoyl)propionic acid in ethanol to give a solid: mp 212°-214° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=1[CH3:37]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=1[CH3:37])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Nc1ccc(O)cc1C
Yield: 76.1 %

Procedure:
A solution of 3-butyryl-4-chloro-8-(4-methoxybenzoyloxymethyl)quinoline (2.56 g, 6.4 mmol) and 4-amino-3-methylphenol (1.18 g, 9.6 mmol) in 1,4-dioxan (30 ml) was heated at reflux for 2 hours, then evaporated. Chromatography (silica gel, 1% methanol in dichloromethane) and recrystallisation from ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)-quinoline, (2.36 g, 76%), m.p. 171°-175°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[NH:6][C:7]=1[I:8])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([N:6]1[C:7]([I:8])=[C:3]([CH:1]=[O:2])[CH:4]=[C:5]1[C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(C=O)c(I)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C=O)c(I)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a stirred solution of 4 (0.72 g, 2.6 mmol) in acetone (20 mL) was added K2CO3 (0.71 g, 5.1 mmol). The resulting mixture was stirred for 30 minutes at room temperature. Benzyl bromide (0.46 mL, 3.8 mmol) was added dropwise to the reaction mixture and was then refluxed for 16 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate and water. The combined organic layer was dried over anhydrous MgSO4, filtered and then concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 5 as a white solid (0.85 g, 90%). 1H NMR (CDCl3) δ 9.66 (s, 1H), 7.50 (s, 1H), 7.24-7.25 (m, 3H), 6.98 (d, J=7.6 Hz, 2H), 5.75 (s, 2H), and 3.72 (s, 3H); 13C NMR (CDCl3) δ 186.98, 160.33, 136.43, 128.97, 128.22, 127.84, 127.10, 126.59, 119.32, 92.81, 52.81, and 52.11.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)(=[NH:4])[NH2:3].[CH3:20][S:21](O)(=[O:23])=[O:22].C(OCC)C>CO>[CH3:20][S:21]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:2](=[NH:3])[NH2:4])=[CH:6][C:7]=1[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)O
Reactant: N=C(N)c1ccc(O)c(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1

Procedure:
In 200 ml of methanol, was suspended the 4-amidino-2-benzoylphenol hydrochloride obtained above. To the suspension was added 60 g of methanesulfonic acid followed by ethyl ether. The precipitated pale yellow crystals were collected by filtration and dried to obtain 109 g of 4-amidino-2-benzoylphenol methanesulfonate.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])(C)C)=[O:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:1]([O:3][CH2:4][CH3:7])=[O:2])[CH:9]=[CH:10]3)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccn2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Commercially available N-Boc-5-indoleboronic acid (0.30 g, 1.1 mmol) was dissolved in CH2Cl2 (20 mL) and pyridine (1 mL) with molecular sieves (activated 4 A) and stirred overnight at RT. Commercially available ethyl 3-t-butyl-1 H-pyrazole-5-carboxylate, Cu(OAc)2 and molecular sieves (4 A activated, powder) were added to the boronic acid solution and the whole stirred at RT open to the atmosphere for 2d. The reaction mixture was filtered through a pad of Celite®, concentrated and purified by column chromatography to yield ethyl 5-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-1H-indole-1-carboxylate (0.18 g, 38% yield). LC-MS (EI) m/z: 412.3 (M+H+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li+].CCC[CH2-].[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:16]1([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C1CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
Diisopropylamine (6.37 mL, 44.7 mmol) in THF (50 mL) was cooled to 0° C. under argon. N-Butyllithium (16.7 mL, 2.5 M in hexane, 41.7 mmol) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of tetrahydro-2H-pyran-4-carboxylic acid (D8) (1.94 g, 14.9 mmol) in THF (10 mL) was added and a white precipitate was formed. The resulting mixture was then heated at 50° C. for 3 h. The reaction mixture was cooled to 0° C. and methyl iodide (2.80 mL, 44.7 mmol) was added dropwise. The reaction was then allowed to warm to rt and left to stir overnight. 10% aqueous citric acid solution (40 mL) was then added and the THF was removed by rotary evaporation. The residual aqueous mixture was extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give the title compound (D9) (1.26 g, 53%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28]([OH:30])=O)=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.C(O)(=O)C.[CH3:35][N:36]([CH3:41])[C:37](=[O:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:41])[C:37]([CH2:38][NH:39][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:23])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:30])=[O:40]
Reactant: CN(C)C(=O)CN
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(=O)NCC(=O)N(C)C)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 51.7 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (37 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (60 mg), glycine dimethylamide acetate (25 mg), HBTU (63 mg), and DIEA (36 uL). LC/MS: m/z 523.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 8.84 (t, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.35 (d, 1H), 7.30 (s, 1H), 4.21 (d, 2H), 4.04 (s, 3H), 3.65 (s, 3H), 3.00 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: C(OC([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:40]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)=[CH:23][CH:24]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N>[CH3:39][O:38][C:34]1[N:33]=[C:32]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[O:26][CH2:27][C:28]2([CH2:29][O:30][CH2:31]2)[C:19]23[CH2:18][O:17][C:16]([NH2:8])=[N:40]2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)CO3)n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
The mixture of di-tert-butyl[6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (160 mg, 0.289 mmol) and TsOH.H2O (275 mg, 1.45 mmol) in MeCN (3.2 mL) was stirred for 4 hours at 40° C. After dilution with CHCl3, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=99:1-95:5) and then the residue was washed with EtOAc to afford 6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (40 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]1[N:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[S:16][CH:17]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:34]>C(Cl)Cl.C(OCC)C>[ClH:34].[ClH:34].[ClH:34].[NH2:7][C@H:8]([C:13]1[N:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[S:16][CH:17]=1)[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)OC(C)(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
1162 mg (2.46 mmol) ((S)—1-{2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-carbamic acid tert-butyl ester was dissolved in methylene chloride (24.6 ml) and 2M HCl in diethyl ether (12.3 ml) was added at room temperature. A solid precipitated. The reaction was stirred at room temperature over night. The reaction was diluted with diethyl ether, stirred for 15 minutes and the solid was filtered off, washed with diethyl ether and dried to yield 1195 mg (100%) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride as a light yellow solid. MS ISP (m/e): 372.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.98 (s, 1H), 9.31 (s, 1H), 8.46 (br s, 3H), 7.93 (s, 1H), 7.66 (s, 1H), 7.47 (d, 1H), 7.31 (d, 1H), 7.13 (s, 1H), 4.27 (m, 1H), 3.90 (s, 3H), 2.35 (s, 3H), 1.94-1.83 (m, 1H), 1.80-1.69 (m, 1H), 1.52-1.39 (m, 1H), 0.90 (d, 3H), 0.86 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19][C:20](O)=O.[OH-].[Na+]>O>[CH3:17][O:18][CH2:19][C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCC(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 200 °C
Reaction time: 0.12 h

Procedure:
3-Amino-4-(2-methylpropylamino)quinoline (5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were mixed and heated at about 200° C. until all bubbling had stopped. Heating was continued for 5-10 min longer and the dark solution was allowed to cool to room temperature. The solution was diluted with water, made strongly basic with 50% sodium hydroxide and extracted with ether. The combined extracts were dried over magnesium sulfate and evaporated to dryness to yield 5.2 g of crude product. The crude product was used as such for further reactions. A small sample was recrystallized from ether to yield nearly colorless crystals, m.p. 96°-99° C.