Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([Br:21])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Br:21][C:12]1[CH:13]=[C:14]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)[O:8][C:9]2=[N:10][CH:11]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C
Yield: 56 %

Procedure:
A sealable tube was charged with (5S)-7-iodo-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (350 mg, 0.764 mmol), pyridin-3-ylboronic acid (94 mg, 0.764 mmol), tetrakis(triphenylphosphine)palladium (20.04 mg, 0.076 mmol) and THF (7641 μL, 0.764 mmol). The mixture was purged with Ar for 2 minutes then a solution of potassium carbonate (1.5 M) (1019 μL, 1.528 mmol) was added and the reaction vessel was sealed and heated at 110° C. for 6 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (5S)-3-bromo-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (175 mg, 0.428 mmol, 56.0% yield) as a brown foam. MS m/z=409.0 [M+H]+. Calc'd for C19H14BrN4O2: 409.0.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.N1C=CC=CC=1>CO.C(Cl)Cl>[CH3:13][C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:3][N:4]=1
Reactant: C1CNCCN1
Reactant: Cc1nnc(Br)n1-c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc(N2CCNCC2)n1-c1ccccc1
Reaction time: 22 h

Procedure:
A mixture of 3-bromo -5-methyl-4-phenyl-4H-1,2,4-triazole (4.16 g), 15.07 g of piperazine and 20 ml of pyridine is stirred at 100° under nitrogen for 22 h. The reaction is monitored by TLC (8% methanol/methylene chloride) and after this period of time no change occurs. The mixture is subsequently placed in a Parr bomb and heated in an oil bath at 180° for 24 h. Bomb pressure increases by 40 psi. The mixture is worked up by partitioning between chloroform and water. The organic phase is washed with saturated aqueous sodium bicarbonate (2×) and with saline (2×), dried over sodium sulfate and concentrated to a solid, the product is recrystallized in ethyl acetate, MS [M+H]+ 243.1484.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=1)[C:40]#[N:41]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=3)[C:40]#[N:41])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#Cc1ccnc(Br)c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc(C#N)ccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromoisonicotinonitrile following a procedure analogous to that described in Example 138 Method 1. LC-MS Method 2 tR=1.419 min, m/z=478.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17 (s, 2H), 2.25 (m, 1H), 2.41-2.58 (m, 2H), 3.06 (m, 1H), 5.58 (m, 1H), 7.08 (d, 2H), 7.25-7.40 (m, 5H), 7.59 (d, 1H), 7.80 (d, 2H), 8.10 (s, 1H), 8.29 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=1[N+:34]([O-:36])=[O:35]>O1CCCC1.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:21]2[C:22]([N+:34]([O-:36])=[O:35])=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
(R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (compound 20) is de-protonated with potassium tert-butoxide (KOtBu) in tetrahydrofuran (THF). The resulting anion is reacted 2-chloro-1,3-dinitro-5-trifluoromethylbenzene (compound 2) in tert-butyl methyl ether (MTBE)/THF. When the reaction is complete, the reaction mixture is quenched with water and partitioned with more MTBE. The organic layer is washed with brine and water and concentrated on a rotary evaporator. The solid concentrate is re-dissolved in methanol and re-precipitated with water. The resulting precipitate is filtered and dried to afford (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester which can be used in the next step without further purification. This reaction has been carried out at a scale using 4.2 Kg of compound 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0° C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid (8.28 g, 63%). 1HNMR (400 MHz, CD3OD, δ): 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][C@@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].Br[CH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1>>[CH3:2][N:3]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:24][CH:25]=1)[C@@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CN[C@@H](C(=O)O)C(C)C
Agent: Cl
Product: CC(C)[C@H](C(=O)O)N(C)Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 74 %

Procedure:
Prepared by reaction of methyl D-valine hydrochloride and tert-butyl 4-bromomethylbenzoate analogously to Example 56, stage a. The compound was obtained in 74% yield after chromatographic purification, FAB-MS: 321 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=3)[C:35]=2[O:36]CCO)[C:30](O)=[O:31])[CH:24]=[CH:25][CH:26]=1.[CH3:47][CH2:48][O:49]C1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1C=CC=CC=1.CCO.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30]([C:29]1[CH:33]=[C:34]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)[C:35]([O:36][CH:48]([OH:49])[CH3:47])=[C:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH:28]=1)=[O:31]
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: NCCCCCCCCSc1nc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CC(O)Oc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCSc2nc3ccccc3o2)cc1-c1cccc(Cl)c1
Yield: 74.1 %

Procedure:
To a flame dried round bottom flask with 8-(benzoxazol-2-ylsulfanyl)octylamine (0.155 g, 0.558 mmol) in benzene:EtOH (1:1, 6 mL) at room temperature was added 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid (0.150 g, 0.372 mmol) followed by EEDQ (0.258 g, 1.04 mmol). After 3 days at this temperature, it was diluted with EtOAc (200 mL). This solution was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (30% EtOAc/petroleum ether) to afford the product (0.183 g, 74%) as a solid; 1H NMR (CDCl3) δ 1.28-1.42 (m, 6H), 1.42-1.68 (m, 5H), 1.77-1.97 (m, 2H), 3.27-3.41 (m, 6H), 3.46 (dd, J=6.1, 13.5 Hz, 2H), 6.09-6.17 (m, 1H), 7.22-7.47 (m, 7H), 7.47-7.54 (m, 2H), 7.54-7.66 (m, 3H), 7.74 (s, 2H); mass spectrum [(+) ESI], m/z 664 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:17]([CH2:18]O)[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([NH:9][C:10]1[S:11][CH2:18][C@@H:17]2[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][C@:13]2([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cccs2)C1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccs2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of racemic tert-butyl 3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-(2-thienyl)pyrrolidine-1-carboxylate (3.8 g, 8.23 mmol) in dichloromethane (206 mL) cooled to 0° C. is added drop wise 1-chloro-N,N,2-trimethylpropenylamine (2.18 mL, 16.46 mmol). The reaction is warmed to room temperature and is stirred for 2 hours. To the reaction mixture is added a saturated solution of sodium bicarbonate and dichloromethane. The mixture is extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (3.30 g, 90%). ES/MS (m/e): 444 (M+H). The racemic tert-butyl-3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (3.2 g, 7.4 mmol) is dissolved in methanol/chloroform (36 ml/25 ml) and is separated into its constituent enantiomers by chiral SFC (Chiralpak OJ-H 50×250 mm; eluent: 25% methanol in 75% CO2; flow 300 g/min at UV 240 nm; column temperature −40° C.; 0.64 g/injection). Analysis of isolated enantiomer (Chiralpak OJ-H 4.6×150 mm; eluent: 25% methanol in 75% CO2; flow 5 mL/min at UV 240 nm, column temperature −35° C.) gave the title compound with Rt=1.5 min, isomer 1, (1.27 g, 39%, >99% ee).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O-:14])=[O:13])[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCNc1ccccc1CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccccc1CC(=O)OC(C)C(=O)OCC

Procedure:
To a warm mixture of 7 g. sodium 2-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 2-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=O)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[S:32])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)N4CCCC4)ccc3n2CC2CC2)cc1
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2nc3cc(C(=S)N4CCCC4)ccc3n2CC2CC2)cc1
Temperature: 100 °C

Procedure:
To a solution of free base 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-5-(1-pyrrolidinylcarbonyl)-1H-benzimidazole (Example 21, from 80 mg 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carboxylic acid) in pyridine (2 mL) was added P2S5 (507 mg, 1.14 mmol). The mixture was heated at 100° C. for 24 h and cooled to room temperature. After being decanted, the supernatant was concentrated and the residue was diluted with EtOAc (20 mL), washed with 1 N NaOH (2×10 mL) and then H2O (2×10 mL). The organic layer was dried over MgSO4 and was evaporated. The crude residue was purified by silica gel column chromatography to give an oil (59 mg, 62% for 2 steps). 1H NMR (400 MHz, CD3OD): δ 7.70 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.27 (s, 2H), 4.08–3.95 (m, 4H), 3.89 (d, J=6.8 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 2.14–2.03 (m, 2H), 2.00–1.92 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.06–0.98 (m, 1H), 0.54–0.48 (m, 2H), 0.28–0.22 (m, 2H). MS (ESI) (M+H)+=420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:46]1([C:49]2[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47]1>CN(C=O)C.O>[CH:46]1([C:49]2[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=3)[C:12]([C:9]3[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[NH:7][CH:6]=[CH:5]4)=[O:14])=[CH:51][CH:50]=2)[CH2:48][CH2:47]1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1c(F)c(Cl)cc2cc[nH]c12)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
To a solution of 37 mg (0.17 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 54 mg of TBTU (0.17 mmol) in 2 ml DMF, were added 0.148 ml (0.87 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 51 mg (0.17 mmol) (4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 43 mg white foam (48%). MS (EI) 514.1 (M)+.
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:40][NH:41][CH3:42].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:40][N:41]([CH3:42])[C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:28][C:17]=12)=[O:26]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added dimethylamine (2M in THF) (0.0386 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid dimethylamide 321 (0.014 g, 0.037 mmol, 97%.) 1H NMR (CDCl3) o9.07 (dd, 1H), 8.18 (d, 1H), 7.65 (dd, 3H), 7.03(dd, 2H), 4.79 (dd, 2H), 4.53 (d, J=17 Hz, 1H), 4.25 (d, J=17 Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H.) MS: 380 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Reactant: Sc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CCCCCCCSc1ccc(Br)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (0.6 g., 2.01 mm), was reacted with 4-bromothiophenol (0.60 g., 3 mm), and triethylamine (1.12 ml, 8.05 mm) in DMF (35 ml) as in Example 14(b) to afford the desired product. This was further purified by flash chromatography over silica gel with ethyl acetate in hexane.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:34][S:35]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCNS(C)(=O)=O)ccc21
Yield: 77.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methanesulfonylamino-ethyl)-amide (57 mg) was prepared by following General Procedure Q starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (75 mg), methanesulfonyl chloride (16 mg), and triethylamine (62 uL). LC/MS: m/z 529.6.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[K+].CO.Cl>C1COCC1>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCCCO1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Caprolactone (100 g) was added to a mixture of potassium hydroxide (145 g), methanol (110 mL), and THF (390 mL). The resulting mixture was stirred at room temperature overnight. The solution was then acidified with HCl and extracted with ethyl acetate. The combined organic layers were washed with water, dried, filtered, and concentrated to obtain 6-hydroxyhexanoic acid. 1H NMR (CDCl3, 500 MHz) δ 1.44 (m, 2H), 1.60 (m, 2H), 1.68 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 5.80 (br, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][CH2:30]Cl>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][O:18][CH2:28][O:29][CH3:30])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1csc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of the product of Example 10B (3.9 g, 13.9 mmol) and diisopropylethylamine (7.42 mL, 43 mmol) in dichloromethane (8 mL) was treated with methoxymethyl chloride (2.38 mL, 32 mmol), stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane to give the title compound (4.32 g, 94%). 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1 H), 7.21 (m, 2 H), 7.13 (m, 3 H), 4.62 (s, 2 H), 4.34 (s, 2 H), 4.20 (s, 2 H), 3.36 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)=[C:24]([F:38])[CH:23]=1)#[N:2].[NH2:39][C:40]1[S:41][CH:42]=[CH:43][N:44]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:14]([O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:39][C:40]4[S:41][CH:42]=[CH:43][N:44]=4)=[O:30])=[C:24]([F:38])[CH:23]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:1]#[N:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nccs1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Phenyl N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (6.93 g) and 2-aminothiazole (2.75 g) were dissolved in dimethylformamide (70 ml), and then diisopropylethylamine (4.8 ml) was added and the mixture was heated and stirred at 90° C. for 2 hours. After cooling, water was added and the precipitated solid was filtered out and washed with ethyl acetate to obtain 5.53 g of the title compound as light brown crystals (79% yield).