Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)=[O:37])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:23]([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(NC(=O)C2CCN(S(C)(=O)=O)CC2)cc1
Yield: 65.1 %

Procedure:
A solution of 4-amino-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (100 mg, 0.268 mmol), 1-(methylsulfonyl)-4-piperidinecarbonyl chloride (108 mg, 0.48 mmol) and DIPEA (138 μL, 0.804 mmol) in DCM (8 mL) was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and triturating with Et2O/pentane gave the title compound (98 mg, 65%). 1H NMR (400 MHz, DMSO δ 10.42 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.82 (dd, J=7.7, 1.9 Hz, 1H), 7.62-7.63 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 1H), 3.63 (d, J=11.8 Hz, 2H), 3.38-3.39 (m, 1H), 3.11 (dd, J=13.4, 4.7 Hz, 1H), 2.90 (s, 3H), 2.76-2.78 (m, 2H), 1.95 (d, J=13.5 Hz, 2H), 1.63-1.68 (m, 2H), 1.44-1.48 (m, 1H), 1.09 (t, J=7.0 Hz, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.7 Hz, 3H). LCMS (m/z, Method B) ES+ 562.0 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:65]([NH2:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C>[CH2:65]([NH:72][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][C:22]2[O:21][CH2:20][CH2:19][N:18]3[CH:17]=[C:16]([C:15]4[N:11]([CH:8]([CH3:9])[CH3:10])[N:12]=[CH:13][N:14]=4)[N:25]=[C:24]3[C:23]=2[CH:26]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)NCc3ccccc3)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a mixture of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid trifluoroacetic acid salt (100 mg, 0.21 mmol), HATU (96 mg, 0.25 mmol) and NEt3 (63 mg, 0.63 mmol) in DMF (2 mL) was added a solution of benzylamine (27 mg, 0.25 mmol) in DMF (0.2 mL) and the resulting mixture stirred at RT for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% tMeOH in DCM) affording 120 as a white solid (78 mg, 84%). LCMS: RT 3.94 min [M+H]+ 443.3. 1H NMR (CDCl3, 400 MHz): δ 8.38 (1H, d, J=2.31 Hz), 7.91 (1H, s), 7.75 (1H, s), 7.27-7.19 (6H, m), 7.04 (1H, d, J=8.36 Hz), 5.89-5.88 (1H, m), 5.79 (1H, s), 4.46-4.43 (6H, m), 3.68 (2H, s), 1.59 (6H, d, J=6.62 Hz)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17](=[O:41])[C@@H:18]([NH:22][C:23](=[O:40])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[C@H:19]([OH:21])[CH3:20].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(Cl)Cl.CO>C1COCC1>[CH3:15][O:16][C:17](=[O:41])[C@@H:18]([NH:22][C:23](=[O:40])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[C@H:19]([OH:21])[CH3:20]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1)[C@@H](C)O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(C#Cc2ccc(CN3CCOCC3)cc2)cc1)[C@@H](C)O
Reaction time: 4 h
Yield: 85.9 %

Procedure:
Sodium triacetoxyborohydride (0.670 g, 3.16 mmol) was added to a solution of benzaldehyde 3 (0.822 g, 2.25 mmol) and morpholine (260 μL, 2.97 mmol) in THF (15 mL) under N2 atmosphere and the reaction monitored by TLC (25:1 DCM/MeOH, Rf=0.2). After stirring 4 h, the reaction mixture was quenched with saturated NaHCO3 (150 mL), extracted with EtOAc (3×100 mL), dried over MgSO4, filtered and concentrated to give a yellow syrup. Purification by silica gel chromatography (35:1 DCM/MeOH) afforded 0.844 g (86% yield) of 4 as a sticky white foam.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46]([O:53][C:54]1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCNC1COC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:54][O:53][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1COC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1COC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (325 mg, 0.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (8 g) (248 mg, 1.07 mmol). The yield was 340 mg, 71%, of a colorless sticky mass.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:20].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(NC(C)C)(C)C>CN(C=O)C.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>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:20])=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:11]=3)[C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]2=3)[CH2:14][CH2:13]1
Reactant: C#Cc1ccccn1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=c1[nH]sc2c1c(=O)c1cc(F)c(C#Cc3ccccn3)cc1n2C1CC1
Temperature: 90 °C

Procedure:
Pd (PPh3)4 (4.5 mg) is added to a stirred solution of 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (23 mg, 0.065 mmole) in DMF (1 mL), followed by the addition of 2-ethynylpyridine (2 equivalents, 0.13 mmole) and diisopropyl amine (0.15 mL.) under argon at room temperature. The reaction tube is sealed and then stirred in a microwave (100 W, 90° C.) until complete as monitored by LC/MS. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is dissolved in a mixture of DMF: CHCl3: MeOH (1:8:1) and precipitated by adding diethyl ether (1-2 ml). This process is repeated three to five times. The resulting solid, 9-cyclopropyl-6-fluoro-7-(2-(pyridin-2-yl)ethynyl) isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione, is washed with water to remove salt. The product is dried and analyzed. HPLC may be needed to obtain adequately pure product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
In a three-neck reactor 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.58 mmol) was dissolved in 36 mL tetrahydrofuran. The mixture was cooled at −78° C. and butyllithium solution (2.5 M in hexane, 3.20 mL, 8 mmol) dissolved in 10 mL was added dropwise over 15 min. The reaction was stirred at −78° C. for 20 min. Then benzyl carbonochloridate (570 μl, 3.99 mmol) was added dropwise. The reaction was stirred overnight. Water was added and the mixture evaporated. The crude was partitioned between ethyl acetate and water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 490 mg (48% yield) of the title compound. Purity 100%.
Reaction SMILES: Cl.[OH:2][NH2:3].C(O)C.C1COCC1.[O:12]=[C:13]([NH:43][CH2:44][C:45](=O)[CH3:46])[CH:14]([NH:27][C:28](=[O:42])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:31][CH:30]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1>CCCCCC>[OH:2][N:3]=[C:45]([CH3:46])[CH2:44][NH:43][C:13](=[O:12])[CH:14]([NH:27][C:28](=[O:42])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:31][CH:30]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1
Reactant: CC(=O)CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1)=NO
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.7 %

Procedure:
Hydroxyamine hydrochloride (20 mg, 0.288 mmol) was added to a solution mixture of ethanol:THF (2:1, V/V, 7.5 mL) containing N-{2-oxo-2-[(2-oxo-propyl)amino]-1-[4-(trifluoromethoxy)benzyl]ethyl}-4-(3,3,3-trifluoropropoxy)benzamide (100 mg, 0.192 mmol) prepared in Example 76. The mixture was stirred at room temperature for 6 hours, and the solvent was evaporated. The residue was purified by thin layer chromatography for separation (ethyl acetate:n-hexane, 2:1, V/V, developed once) to give 49 mg of the title compound (white powder, yield: 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([CH3:15])([CH3:1])[CH2:7]2)=[O:22])=[CH:19][C:18]=1[F:26]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1(C)C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To tert-butyl 2,2-dimethylpiperazine-1-carboxylate (0.902 mmol, 0.193 g) in dichloro-methane (5 mL) was added 4-amino-3-fluorobenzoic acid (0.902 mmol, 0.14 g), and triethylamine (1.805 mmol, 0.252 mL, 0.183 g). To this mixture was added 1-propanephosphonic acid cyclic anhydride (1.805 mmol, 1.074 mL, 1.149 g, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic layer was dried with sodium sulfate, filtered and concentrated under vacuum to give the intermediate tert-butyl 4-(4-amino-3-fluorobenzoyl)-2,2-dimethylpiperazine-1-carboxylate (264 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1>CN(C=O)C>[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccn[nH]2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 7.1 %

Procedure:
DIEA (0.011 mL, 0.062 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.062 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2H-pyrazol-3-yl)-phenylamine (0.009 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.0014 g of product in 7% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (36 mg, 0.18 mmol) in dry DMF (1 ml) DIPEA (54 μl, 0.3 mmol) and then HATU (65 mg, 0.17 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 40 mg, 0.15 mmol) was then added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (57 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:33]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CN1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of EXAMPLE 35 (50 mg, 0.109 mmol) in MeOH (1 mL) was added sodium borohydride (13 mg, 0.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (5% MeOH/DCM) to give the title compound. LC-MS m/z=460.17 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=4.7 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.43-7.37 (m, 5H), 7.32-7.27 (m, 3H), 6.67 (s, 1H), 4.83 (dd, J=10.2 Hz, J=3.6 Hz, 1H), 3.81-3.72 (m, 1H), 3.35 (d, J=11.4 Hz, 1H), 3.01 (d, J=11.8 Hz, 1H), 2.66-2.46 (m, 3H), 2.32-2.22 (m, 1H), 2.21-2.08 (m, 2H), 1.96-1.80 (m, 2H).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:3].[CH:15]([N+:18]1[CH2:22][CH2:21][CH2:20][C:19]=1N(C)C)([CH3:17])[CH3:16].COS([O-])(=O)=O.O>C(O)C.C(OCC)C>[CH2:2]([O:4][C:5]([C:6](=[C:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH:15]([CH3:17])[CH3:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:14])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)[N+]1=C(N(C)C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=C1CCCN1C(C)C)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
Add [dropwise, with stirring, at from 90°-100°, in a stream of nitrogen] a solution of 5.1 g of sodium in 100 ml of ethanol to a mixture of 32 g of 4-chlorophenylacetic acid ethyl ester and 59.13 g of 1-isopropyl-2-dimethylamino-1-pyrrolinium-methylsulfate. After completion of the addition, continue stirring for a further 30 minutes; then cool and take up with water (≈100 ml) and diethyl ether (≈150 ml). Collect the organic phase, extract the aqueous phase once again with diethyl ether, combine the ether extracts, dry and concentrate them to obtain a yield [45.6 g (92% of theory)] of crude title compound; recrystallize 5 g from ethanol/water to obtain 4.2 g of product with a m.p. of 70° to 71°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=1.[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([N:29]=[C:30]=[O:31])(=[O:28])=[O:27])=[O:19].[CH3:32]COCC>>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:32][O:12]2)[N:3]=[C:2]([NH:1][C:30]([NH:29][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]([O:17][CH3:16])=[O:19])(=[O:27])=[O:28])=[O:31])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(COC2CCCO2)nc(N)n1
Reactant: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC2CCCCO2)n1
Reaction time: 3 h

Procedure:
To a solution of 3.25 g of the product from Example 3 in 50 ml of ether was added 3.75 g of 2-methoxycarbonylbenzenesulfonyl isocyanate and the mixture was stirred for 3 hours under nitrogen. The precipitated product was filtered and washed with ether to afford 6.0 g of the title compound, m.p. 126°-128°(d).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH:16]1[C:29]3[CH:28]=[CH:27][C:26]([C:30](=[NH:36])[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:25][C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)=O)(C)(C)C.O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClC(Cl)C>[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][CH:11]([CH:16]1[C:29]3[CH:28]=[CH:27][C:26]([C:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[NH:36])=[CH:25][C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CCN(CC)C(=N)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=N)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To solution of crude 3-[3-(N,N-diethyl-carbamimidoyl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 3m (0.34 g) in dichloroethane (2 mL) was added H2O (0.1 mL) and TFA (2 mL). The mixture was stirred at rt for 1 h and evaporated. The residue was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA), yielding 0.263 g (56%) for two steps) of 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-9H-xanthene-3-carboxamidine, 4m as a TFA salt (MS m/z (MH+) 390.3.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:42])[CH2:41][O:40][CH2:39]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][O:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2ccccn2)COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)COC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.045 g, 0.107 mmol, 1.0 eq) and 3-(pyridin-2-yl)oxetan-3-amine.2HCl (0.025 g, 0.112 mmol, 1.05 eq) in DMF at 0° C. was added TEA (0.15 ml, 1.08 mmol, 10 eq) and BOP reagent (0.06 g, 0.136 mmol, 1.3 eq). The reaction mixture was stirred as rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC. Yield: 0.015 g (25.4%).