Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:7]=1[F:24])[CH3:2].[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:7]=1[F:24])[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Yield: 94 %

Procedure:
steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=1.[OH-].[Na+]>COCCO>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]2[N:34]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:33]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(NC(=N)N)cn1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2sc(C)nc2CC3)cn1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 0.76 mmol), N-(6-methoxy-pyridin-3-yl)-guanidine nitrate (192 mg, 0.84 mmol), NaOH (34 mg, 0.84 mmol) and 2-methoxyethanol (2 mL) was heated at 100° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a white solid (20 mg, 8%): mp 210-211° C. Anal. RP-HPLC: tR 11.6 min (10-70% MeCN, purity 93%). 1H-NMR (CDCl3): δ 8.42 (d, 1H, J 2.4, Ph-H), 8.26 (s, 1H, Py-H), 8.08 (dd, 1H, J 9.1, 2.9, Ph-H), 7.19 (brs, 1H, NH), 6.86 (d, 1H, J 9.1, Ph-H), 4.04 (s, 3H, OMe), 3.13 (m, 4H, CH2—CH2), 2.87 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.47, 159.97, 159.38, 159.12, 157.10, 155.16, 137.95, 131.90, 130.45, 128.62, 116.48, 110.33, 53.49, 25.29, 23.92, 19.84. MS (ESI+): m/z 326.08 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:22]1[CH2:27][CH:26]=[C:25]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[C:36]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4[nH]cc(C5=CCNCC5)c4c3)ncc21

Procedure:
The title compound was prepared using Buchwald reaction from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.31 (m, 4 H) 1.65 (m, 8 H) 2.02 (m, 3 H) 2.98 (br. s., 2 H) 3.46 (s, 3 H) 4.02-4.25 (m, 2 H) 4.88 (br. s., 2 H) 6.26 (s, 1 H), 6.65 (d, J=8 Hz, 1 H), 7.10 (s, 1 H), 7.98 (s, 1 H) 8.34 (d, J=8.0 Hz, 1 H) 8.45 (s, 1 H). [M+H] calc'd for C26H29F2N7O, 494; found 494.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].OS(O)(=O)=O.N([O-])=O.[Na+].[BrH:29]>O>[Br:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Br)c(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of EXAMPLE 144B (8.3 g) was added water (75 mL) and H2SO4 (25 mL). The mixture was stirred at 0° C. while NaNO2 (3.13 g) in water (30 mL) was added. After stirring for 1 hour, the mixture was added to CuBr (5.45 g) in 48% HBr (200 mL). This mixture was stirred at 60° C. for 3 hours, cooled to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with aqueous Na2CO3 and dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:38][CH:39]=1)=[O:8]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 70.7 %

Procedure:
To 0.193 g (1.2 mmol) of 3-methylthiophene-2-carbonyl chloride in 3 ml of dichloromethane, cooled to 0° C., is added 209 μl of triethylamine. The mixture is stirred and 0.30 g (1 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine is added. The mixture is stirred at room temperature overnight and then concentrated under vacuum. To the residue is added 30 ml of ethyl acetate and the mixture washed with 2 ml each of water 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried (Na2SO4) and the solvent removed to give 0.30 g of solid. The solid is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 150 mg of product as a yellow foam.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:34][NH:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([OH:33])=O)[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:50][C:51]1([CH2:54][OH:55])[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([NH:14][C@H:15]([CH2:34][NH:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:31]([NH:50][C:51]1([CH2:54][OH:55])[CH2:53][CH2:52]1)=[O:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC1(CO)CC1
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-dodecanamido-3,12-dioxo-1-phenyl-2-oxa-7-thia-4,11-diazatricosane-5-carboxylic acid (1 eq) in DCM (0.1 M) was added (1-aminocyclopropyl)methanol hydrochloride (1.3 eq), DIEA (2.5 eq) and HBTU (1.2 eq). The reaction was stirred at room temperature for 2 hours then concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex, then 0-10% MeOH/DCM to afford the title compound as an off-white solid.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred solution of 1.3 g of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (Example 4) and 550 mg of triethylamine in 15 ml of tetrahydrofuran is added 765 mg of benzoyl chloride. After allowing the mixture to stir at room temperature overnight it is evaporated and the residue taken up in 100 ml of water. The mixture is extracted with diethyl ether, washed successively with water and brine, dried and evaporated, to yield 2-benzoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 137°-139° after recrystallization from isopropanol.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH:1]1([C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1CCc2ccccc21)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from indane-1-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 403.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[NH:10][C:9](=O)[N:8]=1.P(Br)(Br)([Br:32])=O>[OH-].[Na+]>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=[C:9]([Br:32])[N:8]=1
Reactant: O=c1nc(Oc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)[nH]1
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cccc(Oc2cc(Oc3cccc(C(F)(F)F)c3)nc(Br)n2)c1

Procedure:
4,6-Bis(3-trifluoromethylphenoxy)-pyrimidin-2-one (4.0 g, 0.0096 mol) and POBr3 (100g) were heated at 140° C. for 48 hours. The mixture was then poured onto a mixture of 2N NaOH (500 ml) and ice. The product was extracted into diethyl ether, dried using Na2SO4, filtered and concentrated under reduced pressure. The product was obtained by column chromatography (3:1, hexane: ethyl acetate) and recrystallization (ethyl acetate/hexane). Yield: 1.0 g (22%); melting point 126°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH:37]3[CH2:39][CH2:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: NC1CC1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12
Agent: CCOP(=O)(C#N)OCC
Product: Cn1cc(C(=O)NC2CC2)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5-chloro-1H-indazol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent Mass: 547.19 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 12.4 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with methanesulfonyl chloride (0.46 mL, 5.9 mmol) to provide 0.16 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as an off white solid, m.p. 229.4-230.5° C. Analysis: Calculated for C16H21N5O2S.0.25 H2O: % C, 54.60; % H, 6.16; % N, 19.90; Found: % C, 54.80; % H, 6.24; % N, 19.58.
Reaction SMILES: CC#N.[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
Dry CH3CN (50 mL) was added to 2-(4-hydroxybenzoyl)benzoic acid methyl ester (3.65 g, 15 mmol) followed by cesium carbonate (5.4 g, 16.5 mmol) and trimethylsilylethoxymethylchloride (2.9 mL, 16.5 mmol). The system was stirred at room temperature under nitrogen for 24 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with water (3×50 mL), brine (40 mL) and dried with MgSO4. The solvent was removed and the crude product was purified by flash column chromatography (5:95 EtOAc:petrol) to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid methyl ester as a yellow oil (3.94 g, 10.2 mmol, 67%); Rf 0.79 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 282, Abs 1.072. IR: 2939, 1720, 1666, 1589, 1489 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.94 (m, 2H, R—O—CH2—CH2—Si), 3.66 (s, 3H, COOCH3), 3.75 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.05 (m, 2H, Ar—H), 7.37 (m, 1H, Ar—H), 7.53-7.66 (dtd, 2H, J=22.6, 7.4, 1.4 Hz, Ar—H), 7.72 (m, 2H, Ar—H), 8.05 (m, 1H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ −2, 16.8, 51.5, 65.3, 91.5, 115.1, 127, 128, 129, 129.2, 129.6, 130.4, 132, 140.7, 160.2, 165.2, 194. LC/MS-ES+ m/z 163.2, 297.1, 387.1 [MH+], 409 [MNa+]. HRMS (EI) m/z Calcd. for C21H26O5Si: 386.1549. Found 386.1562.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][N:20]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 4-fluoronitrobenzene (4.74 g) and 6-(methylsulfonyl)pyridin-3-ol (6.4 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (9.3 g), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (9.88 g, yield 100%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([NH:23][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH2:1]([N:8]([CH2:10][C:11]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][C:14]([N:23]([CH3:33])[CH3:24])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1(c2ccccc2)CCC(CN(C)Cc2ccccc2)(c2ccccc2)CC1
Reactant: BC#N
Agent: C=O
Agent: [Na]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from step 10 (diastereomer mixture) (0.350 g, 0.878 mmol) and formalin (1.23 mL, 37% aqueous solution) in acetonitrile (15 mL) was mixed in portions with sodium cyanoboron hydride (0.250 g, 3.86 mmol) and stirred for 45 min at room temperature. Conc. acetic acid was then added until a neutral reaction occurred and the mixture was subsequently stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (3×40 mL). The organic solution was dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by Chromatotron and with cyclohexane/ethyl acetate 1:1. Separation of the diastereomers could not be achieved.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)=O>[CH:1]([NH:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:3]
Reactant: CCOC(=O)C(N)(CC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)C(CC)(NC=O)c1ccccc1
Reaction time: 15 h
Yield: 100 %

Procedure:
12.72 mL of formic acid then 25.38 mL of acetic anhydride were added dropwise, under stirring, to 2.49 g (12.03 mmol) of amine 6. After 15 h at room temperature, solvents were removed under reduced pressure to give 3.09 g of 7 as a green viscous oil (100% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride 1 (5 g, 32.13 mmol) in CH2Cl2 (100 mL) was added with TEA (1.1 mol eq, 4.9 mL) and the mixture stirred at r.t. for 10 minutes. Then 4-fluorobenzensulfonyl chloride (1 mol eq, 6.26 g) and additional TEA (1.1 mol eq) were added and the resulting solution heated at 50° C. for 6 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase finally extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The residue was recrystallized from ethyl ether to afford 2A as white solid (7.10 g, 80% yield). 1HNMR (DMSO, 200 MHz) δ 3.48 (s, 3H), 3.53 (m, 2H), 3.86 (t, 1H), 5.07 (t, 1H), 7.41 (m, 2H), 7.83 (m, 2H), 8.33 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.Cl[C:34]([O:36][C:37]([CH3:39])=[CH2:38])=[O:35].O>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]([CH3:39])=[CH2:38])[CH:11]=2)[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:18]([F:31])=[CH:17][C:16]=2[CH3:32])[C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C)cc2cnc(N)cc21
Reactant: C=C(C)OC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1C)c(=O)n2CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (0.35 g, 0.811 mmol) in pyridine (5 mL) was treated with isopropenyl chloroformate (0.147 g, 1.217 mmol) and stirred at RT for 1 h. Water was added, the mixture stirred for 10 minutes and the resulting solid was collected via filtration and dried to afford prop-1-en-2-yl (1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (360 mg, 86% yield). MS (ESI) m/z: 516.2 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:9]([N:12]=C=O)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:9](=[O:11])(=[O:10])[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 59.9 %

Procedure:
To a solution of phenol (5.01 g, 53.2 mmol) in toluene (25 ml) was added a solution of chlorosulfonyl isocyanate (7.9 g, 55.9 mmol) in toluene (30 ml) at room temperature. The mixture was stirred at 120° C. for 14 hours. The solvent was removed in vacuo and the residue was added dropwise to water (75 ml). After stirring the resultant mixture at room temperature for 24 hours, the resulting precipitate was collected, washed with water, dissolved in EtOAc, washed with brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1) to give sulfamic acid phenyl ester (5.52 g, 60%).