Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Br:19])[CH:17]=[N:18][C:12]=2[NH:11][C:10](=[O:20])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:30]>>[ClH:30].[Br:19][C:16]1[CH:17]=[N:18][C:12]2[NH:11][C:10](=[O:20])[CH2:9][N:8]([CH2:7][C:6]([OH:21])=[O:5])[CH2:14][C:13]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)CN1CC(=O)Nc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of (7-bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid tert-butyl ester (1.61 g, 4.52 mmol) in CH2Cl2 (20 mL) was treated with TFA (15 mL). After stirring at room temperature for 1 h, the solution was concentrated in vacuo. The resulting slurry was treated with anhydrous HCl (40 mL of a 4.0 M) and sonicated for 1.5 h, diluted with Et2O and stirred for 1 h. The solid was isolated by filtration, washed with Et2O, and dried under vacuum at 50° C. overnight to give the title compound (1.66 g, 98%) as a white solid: MS (ESI) m/e 300 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16]([NH:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[O:17]
Reactant: CC(C)[C@@H](O)C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 4-[(1S)-1-aminoethyl]-benzoic acid, methyl ester (5.8 g; 49.1 mmol), (2R)-2-hydroxy-3-methyl-butanoic acid (9.3 g; 51.9 mmol), 1-hydroxybenzotriazole (0.82 g; 6.1 mmol), and triethylamine (22 mL; 158 mmol) in CH2Cl2 (120 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2 g; 74.1 mmol). The cloudy mixture is stirred at room temperature overnight. The reaction mixture is washed with 1N HCl (2×150 mL) then brine. The organic layer is dried over MgSO4, filtered, concentrated, and dried under high vacuum to provide the title compound as a white solid (10.24 g, 75%). This material is used in the next step without further purification. MS (m/z): 280.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:18]([C:14]1[C:15]2[N:11]3[C:10](=[CH:35][C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:12]3[C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]([OH:8])=[CH:17][CH:16]=2)[CH3:19]
Reactant: [H][H]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(-c2ccc(O)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(O)ccc1n32
Yield: 85.4 %

Procedure:
A suspension of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((8-piperidinooctyloxy)-methyl)pyrrolo[2,1,5-cd ]indolizine (0.30 g, 0.44 mmol) and 30 mg 10% palladium on charcoal in 12 ml of ethanol and 8 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by column chromatography over netural aluminium oxide activity grade I, using 10% of methanol in dichloromethane as the eluent. The product was crystallised from dichloromethane, diethyl ether and petroleum ether to afford 189 mg (85%) of 1-ethyl-5-hydroxy-2-(4-hydroxyphenyl)-3-((8-piperidinooctyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 91-95° C. (decomp.). MS(FAB): m/z 503 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ:1.17-1.71 (m, 21H); 2.61-3.09 (m, 8H); 3.38 (t, 2H); 4.68 (s, 2H); 6.92 (d, 2H); 7.12 (d, 1H); 7.22 (s, 1H); 7.48 (d, 2H); 7.83 (d, 1H); 9.58 (s, 1H); 10.59 (s, 1H).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].O[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>CO.N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(S(N)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.7 %

Procedure:
A mixture of 4.7 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.5 g of p-hydroxybenzene sulfonamide, 4.1 g of dicyclohexylcarbodiimide, 10 ml of dry dimethylformamide and 20 ml of dry pyridine was stirred at room temperature for 24 hours. After removal of any insoluble materials, the solvent was removed. The residue was treated with ethyl acetate and then with ether to give crystals. The crystals were dissolved in methanol, and any insoluble materials were removed by filtration. Ether was added to the filtrate to obtain 4.5 g (yield: 57.7%) of p-aminosulfonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as yellow crystals having a melting point of 206° to 209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:21])[CH2:17][NH:18][CH2:19][CH3:20])[C:11]1[CH:10]=[C:9]([C:22]#[N:23])[CH:8]=[CH:7][C:6]=1[S:5]2.I[CH2:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:21])[CH2:17][N:18]([CH2:25][CH3:26])[CH2:19][CH3:20])[C:11]1[CH:10]=[C:9]([C:22]#[N:23])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: CCNCC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (5 g), iodethane (2.2 cc) and sodium carbonate (2 g) in dimethylformamide (50 cc) is charged, and the mixture is brought for 9 hours to 160° C. After cooling, the reaction mixture is poured into a mixture of distilled water (500 cc) and ethyl acetate (500 cc). The organic phase is separated after settling has taken place, washed with distilled water (4×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH3:2].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([NH:19][S:20]([CH2:23][C:24](O)=[O:25])(=[O:22])=[O:21])=[CH:17][CH:16]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:24](=[O:25])[C:23]([S:20]([NH:19][C:18]1[CH:27]=[CH:28][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:22])=[O:21])=[CH:7]2)[CH3:2]
Reactant: CCOc1cccc(C=O)c1O
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(OC)cc3)c(=O)oc12

Procedure:
A solution of 3-ethoxysalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 206-209° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#N)=[CH:13][CH:12]=1.C([O:25][C:26](=O)[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28])(=O)C>>[OH:28][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([N:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:18][CH2:17][C:14]1[CH:15]=[N:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=1)=[O:25]
Reactant: Cc1ccc(N)cn1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)cn1

Procedure:
In analogy to example 49, 6-Methyl-pyridin-3-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled and hydrolysed to give the target compound. MS(m/e): 416.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1)#[N:2].C(N(CC)CC)C.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34]>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[C:7]2[CH:24]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCN(c3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N'-phenylethylenediamine (0.36 g, 1.12 mmole, from Example 21, part A) and triethylamine (0.12 g, 1.18 mmole) in methylene chloride (4 ml) cooled to 0° C. was added a solution of 4-nitrophenyl chloroformate (0.24 g, 1.18 mmole) dissolved in methylene chloride (3 ml). The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous HCl solution. The organic phase was washed with 2N NaOH solution, saturated NaCl solution, dried over MgSO4 and solvent evaporated to obtain 420 mg of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (4:1) to obtain 0.30 g of the title compound as a pure white solid. m.p.=166-168° C. 1H NMR (DMSO-d6) δ7.61 (m,4H), 7.35 (m,2H), 7.03 (m,1H), 6.95 (d, J=8.21 Hz, 1H), 5.21 (dd, J=6.45 and 11.73 Hz, 1H), 3.88 (m, 2H), 3.36 (m 1H), 3.14 (m, 1H), 2.03 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (DMSO-d6) δ158.08, 157.13, 140.58, 132.86, 131.56, 128.63, 121.86, 121.63, 119.15, 118.52, 117.05, 102.54, 77.31, 44.68, 42.06, 36.56, 34.06, 29.36, 24.01; MS: (M+H)+ @348.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[Br:12].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=1>CN(C)C=O>[Br:12][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=1[O:8][CH2:9][CH2:10][O:11][C:16]1[N:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=1
Reactant: CSc1cnc(Cl)nc1
Reactant: Nc1ncnc(OCCO)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cnc(OCCOc2ncnc(N)c2Br)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
To a solution of 2-(6-amino-5-bromopyrimidin-4-yloxy)ethanol (611 mg) in dimethylformamide (20 ml) is added sodium hydride (60% dispersion-type, 125 mg), and the mixture is stirred for 20 minutes. To the mixture is added 2-chloro-5-methylthiopyrimidine (461 mg), and the mixture is stirred at room temperature for three hours. To the mixture is added ice-water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=20:1), and crystallized from ethyl acetate/diisopropyl ether to give 5-bromo-6-[2-(5-methythiopyrimidin-2-yloxy)ethoxy]pyrimidine-4-amine (501 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([OH:13])=O)[N:4]=1.S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([Cl:16])=[O:13])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)nc(C(=O)O)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(=O)Cl)n1

Procedure:
A mixture consisting of 1.1 g (6.0 mmol) of 4,6-dimethoxypyrimidine-2-carboxylic acid, obtained in accordance with a method descibed in the specification of WO 9318012 A1, 1.1 g (9.0 mmol) of thionyl chloride, one drop of N,N-dimethylformamide and 5 ml of toluene was stirred under heating and refluxing for 3 hours. After the reaction, excess thionyl chloride and the solvent were removed under reduced pressure to obtain crystal of 4,6-dimethoxypyrimidine-2-carbonylchloride. In a separate vessel, 0.30 g (2.0 mmol) of 6,6-difluoro-5-methyl-5-hexenole and 0.61 g (3.0 mmol) of 4,6-dimethoxypyrimidine-2-carbonylchloride were dissolved in 10 ml of tetrahydrofuran, followed by the drop-wise addition of 0.40 g (4.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:7) to obtain 0.20 g (yield: 21%) of 6,6-difluoro-5-methyl-5-hexenyl 4,6-dimethoxypyrimidine-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:37]=[N:36][C:35]2[NH:34][C:33](=[O:38])[C:32]([CH3:40])([CH3:39])[O:31][C:30]=2[CH:29]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:39][C:32]1([CH3:40])[O:31][C:30]2[CH:29]=[C:28](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[O:9][C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[C:12]=3[CH3:13])=[O:6])[CH:37]=[N:36][C:35]=2[NH:34][C:33]1=[O:38]
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)C(=O)N3)oc2ccccc12
Yield: 44.6 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.231 g, 1.01 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.28 mL, 1.64 mmol) and 7-bromo-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.200 g, 0.775 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.017 g, 0.078 mmol) and P(o-tol)3 (0.047 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with H2O (100 mL). The resulting solids were collected by filtration and washed with Et2O (50 mL). Residual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/MeOH) the resulting solution concentrated to reveal a light orange solid. The solid was triturated with Et2O and dried to give the title compound (0.14 g, 46%) as a light pink solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.20-8.19 (m, 1H), 7.97-7.93 (m, 1H), 7.57-7.48 (m, 3H), 7.28-7.23 (m, 3H), 5.00-4.78 (m, 2H), 3.17-2.92 (m, 3H), 2.62 (s, 3H), 1.44 (m, 6H); MS (ESI) m/e 406 (M+H)+.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([C:26]3[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=3)[N:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[C:20]=23)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>N.CC(O)C>[NH2:1][C:21]1[C:20]2[N:19]([C:18]([C:26]3[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=3)=[N:17][C:16]=2[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OCc1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(-c3cccc(CO)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 110 °C
Yield: 89 %

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of {3-[1-(3-benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol (366 mg, 0.829 mmol) in NH3/i-PrOH (2M, 5 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 19 h. After excess NH3/i-PrOH was removed in vacuo, the residue was suspended between CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous MgSO4, and filtered. The crude material was purified by filtration through a plug of silica gel, eluting with 5% MeOH:CH2Cl2 (400 mL), concentrated in vacuo, giving 311.5 mg (89%, 0.737 mmol) of the title compound, as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 4.80 (s, 2H), 5.09 (s, —NH2), 5.16 (s, 2H), 7.05-7.09 (m, 1H), 7.11 (d, J=4.8 Hz, 1H), 7.29-7.37 (m, 3H), 7.37-7.48 (m, 5H), 7.47-7.51 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.73-7.78 (m, 1H), 7.86 (s, 1H); MS (ES+): m/z 423.0 (100) [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:22])(=[O:21])[NH2:20])[C:10]=1[NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:31](O)[CH3:32]>>[CH2:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:22])(=[O:21])[NH2:20])[C:10]=1[NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:31][CH3:32])=[O:6])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)c1
Reactant: CCO
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2cccc(C)c2)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3-amino-5-sulphamyl-4-(m-toluidino)-benzoic acid (1.5 g), benzyl bromide (2.5 g), and anhydrous ethanol (50 ml) was heated under reflux for 10 hours. The resulting solution was cooled, and the precipitated ethyl 3-benzylamino-5-sulphamyl-4-(m-toluidino)-benzoate was collected by suction. After recrystallization from ethanol, the compound had a melting point of 169-170°C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([CH3:15])[N:12]=[C:13]([CH3:14])[C:3]=12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C[N:23](C=O)C>>[CH3:15][N:11]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([NH2:23])=[O:10])[C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:3]2[C:13]([CH3:14])=[N:12]1
Reactant: Cc1nn(C)c2ncc(C(=O)O)c(Cl)c12
Reactant: C1COCCN1
Reactant: CN(C)C=O
Product: Cc1nn(C)c2ncc(C(N)=O)c(N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxylic acid (450 mg) and morpholine (870 mg) in DMF (15 mL) was stirred at room temperature for 5 h, and then concentrated under reduced pressure. The residue was treated with water (10 mL), and the resulting solid was filtered, washed with water, and dried under high vacuum. The solid was suspended in anhydrous dichloromethane (20 mL) and treated with oxalyl chloride (1.0 mL) and anhydrous DMF (0.1 mL). The mixture was stirred at room temperature for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was cooled in an ice-bath and slowly treated with a saturated solution of ammonia in THF (20 mL). The suspension was removed from the ice-bath, stirred at room temperature for 1 h, and filtered. The solid was washed with water and dried under high vacuum to give 1,3-dimethyl-4-morpholin-4-ylpyrazolo[5,4-b]pyridine-5-carboxamide as a white powder. A portion of this material (0.33 g) was dissolved in hot toluene (30 mL) and azeotropic for 1 h. The solution was cooled to room temperature and treated with 4-fluoro-3-(trifluoromethyl)phenylisocyanate (0.27 g). The mixture was refluxed for 16 h and then cooled to room temperature. The precipitated solid was filtered, washed with toluene, and dried under high vacuum to give the title compound as a white powder.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH2:13]([O:15][C:16](=[O:35])[C@H:17]([OH:34])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[CH2:28][CH2:27]2)=[C:22]([F:33])[CH:21]=1)[CH3:14]>C(#N)C>[CH2:13]([O:15][C:16]([CH:17]1[O:34][C:6](=[O:7])[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:27]=[CH:28][C:29](=[O:32])[CH2:30][CH2:31]3)=[C:22]([F:33])[CH:21]=2)[CH2:18]1)=[O:35])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)[C@H](O)CNc1ccc(N2C=CC(=O)CC2)c(F)c1
Solvent: CC#N
Product: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
CDI (162.0 mg, 1.0 mmol) is added with stirring to a solution of 3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenylamino]-2(R)-hydroxypropionic acid ethyl ester (Step 5, 146.0 mg, 0.45 mmol) in acetonitrile (4.0 mL), and the mixture is stirred at room temperature overnight. Solvent is removed under vacuum, and the residue partitioned between EtOAc (30 mL) and aq. 3% citric acid (30 mL). The aqueous layer is extracted with EtOAc (2×30 mL), and the combined organic layers are washed with water and saline and dried (MgSO4). EtOAc is removed under vacuum to afford the crude 3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester which is used in the next step w/o further purification (MS (m/z): 349 [M+H]+). The ester intermediate is taken up in 2M methanolic ammonia (8.0 mL, 16.0 mmol), and the resulting solution heated in a closed vial at 60° C. for 1 h. Volatiles are removed under vacuum, and the crude material purified by silica gel chromatography (eluent: 2% MeOH in CH2Cl2) to afford the title compound (55.0 mg, 38% for two steps) as white crystals, MS for C15H14FN3O4 m/z 320 (M+H)+; 1H NMR (CD3CN): δ 2.51 (m, 2 H), 3.89 (m, 2 H), 4.05 (m, 1 H), 4.24 (dd, 1 H), 4.97 (m, 1 H), 5.03 (d, 1 H), 6.18 (br. s, 1 H), 6.72 (br. s, 1 H), 7.20-7.40 (m, 3 H), 7.57 (d, 1 H).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]=1[C:14]#[N:15].CCN(CC)CC>C(Cl)Cl>[S:2]([NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:13]=1[C:14]#[N:15])(=[O:4])(=[O:3])[NH2:5]
Reactant: COc1ccc(COc2cccc(N)c2C#N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(COc2cccc(NS(N)(=O)=O)c2C#N)cc1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of chlorosulfonyl isocyanate (212 mg, 1.50 mmol) in CH2Cl2 (0.55 mL) at 0° C., was added formic acid (0.575 mL) under N2. The reaction was stirred for 30 min, and a solution of 2-amino-6-(4-methoxybenzyloxy)benzonitrile (Example 114b) (191 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added at 0° C., followed by Et3N (0.627 mL, 4.50 mmol). After 30 min, the reaction was concentrated in vacuo and diluted with water. The pH was adjusted to 7 with concentrated HCl, and purified by reverse phase HPLC (10-90% acetonitrile in water) to provide 2-sulfamoylamino-6-(4-methoxybenzyloxy)benzonitrile (130 mg, 52%). 1H NMR (400 MHz, MeOD) δ 3.80 (s, 3H), 5.15 (s, 2H), 6.88 (d, J=8.1 Hz 1H), 6.94 (m, 2H), 7.40 (m, 2H), 7.48 (t, J=8.7 Hz, 1H), 7.75 (dd, J=8.6, 0.8 Hz, 1H).