Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:29][C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[CH:30]=[CH:31][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 60.9 %

Procedure:
Using the procedure described in Example 93, Part A, 4-anisoyl chloride (2.2 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 441 mg (61%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2=[N:14][C:15]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:17]=[C:12]2[CH2:11][CH:10](OC(=O)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O>[N:36]1([CH:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:13]3=[N:14][C:15]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[N:17]=[C:12]3[CH2:11]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(=O)OC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(C(=O)OC(C)(C)C)C1
Reactant: C1CCNCC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-7-acetoxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 5)(210 mg, 0.443 mmol) was treated with piperidine (4380 μl, 44.3 mmol). The resulting pale yellow suspension was sonicated and then stirred at room temperature overnight. The resulting solution was added to water (100 ml) and extracted with DCM (×3), passing the organic extracts through a phase separating column. The filtrate was concentrated under reduced pressure and purification of the crude material by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH:30]1[CH2:33][CH:32]([OH:34])[CH2:31]1.C(O)C>C1COCC1>[ClH:1].[OH:34][CH:32]1[CH2:33][N:30]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:31]1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CC(O)C2)ncn1
Reaction time: 1 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23, 94 mg (0.7 mmol) of N,N-diisopropylethylamine and 80 mg (0.7 mmol) of azetidin-3-ol hydrochloride are suspended in 3 ml of THF and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 20 min. 2 ml of ethanol are then added, and the mixture is again reacted in a single-mode microwave oven (CEM Explorer) for 20 min. The mixture is then reacted initially at 120° C. for a further 60 min and then at 175° C. for 60 min in a single-mode microwave oven (CEM Explorer). The mixture is then separated directly by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator, and the residue is dried under high vacuum. The residue is then stirred in 5 ml of a 4 N solution of hydrogen chloride in dioxane for 30 min. The solid is filtered off, washed with tert-butyl methyl ether and dried under high vacuum.
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][C:19](=O)[CH2:20][CH3:21])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[CH:23]([NH2:26])([CH3:25])[CH3:24].[H][H]>[Pd].CO>[C:1]([C:4]1([CH2:17][CH2:18][CH:19]([NH:26][CH:23]([CH3:25])[CH3:24])[CH2:20][CH3:21])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: CC(C)N
Reactant: CCC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCC(CCC1(C(N)=O)c2ccccc2-c2ccccc21)NC(C)C

Procedure:
A mixture of 14.6 g. of 9-carbamoyl-9-(3-oxopentyl)fluorene from Example 7 and 14.8 g. of isopropylamine in 100 ml. of methanol containing 3.7 g. of 5% palladium on charcoal was heated at 80° C. for eight hours at 750 psi hydrogen. The reaction mixture was cooled, filtered and concentrated to a volume of about 25 ml. The product was added to ethyl acetate and diethyl ether. The organic solution was extracted with 6N hydrochloric acid. The acidic extracts were combined, cooled in ice and made alkaline by addition of 10% sodium hydroxide. The alkaline solution was extracted several times with 50% ethyl acetate in diethyl ether. The extracts were combined, washed with water, dried and concentrated to dryness to provide 4.0 g. of the title compound. The product was dissolved in 50 ml. of ethyl acetate and stirred while 1.38 g. of maleic acid were added. The precipitated solid was collected by filtration and dried to afford 4.0 g. of 9-carbamoyl-9-(3-isopropylaminopentyl)fluorene maleate. m.p. 161°-163° C.
Reaction SMILES: [Br-].[CH2:2](OC1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCC.C([Li])CCC.[CH2:43]([O:45][C:46](=[O:57])[CH:47]=[C:48]([CH3:56])[CH:49]=[CH:50][CH:51]=[C:52]([CH:54]=O)[CH3:53])[CH3:44].CO>O1CCCC1.CCCCCC>[CH2:43]([O:45][C:46](=[O:57])[CH:47]=[C:48]([CH3:56])[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[CH:54]=[CH2:2])[CH3:44]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCCCCCCCCOc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: C=CC(C)=CC=CC(C)=CC(=O)OCC
Temperature: -40 °C
Yield: 119 %

Procedure:
A solution of [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (150 g) in tetrahydrofuran (1100 mL) was cooled to -50° C. to yield a fine suspension of the solid salt. To this mixture was added a solution of n-butyllithium in hexane (180 mL, a 1.6 molar) to yield a solution of the ylide. The mixture was then stirred a further15 min at -40° C., cooled to -70° and treated with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (65 g) dissolved in tetrahydrofuran (250 mL). Addition of hexane and aqueous methanol (40%) to the reaction mixture follwed by concentration of the hexane extract yielded ALL(E)-9-[2-nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (64 g, 58% yield), mp 52-53° C. This ester was then hydrolized by forming a solution of this ester (70 g) in ethanol (1000 mL). This solution was treated with aqueous potassium hydroxide (80 g in 400 mL water) and heated at reflux for 1 h. Water and aqueous mineral acid was then added and the solids were extracted into chloroform. Concentration of this organic extract and crystallization of the residue from an ethyl acetate hexane mixture yielded All(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid (38 g), mp 102-103° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.N[C@H:10](CC)C(O)=O.N[C@H](CC)C(OC)=O.COC(C1CCCN1)=O.[Cl:33][C:34]1[N:39]=[C:38](Cl)[C:37]([N+:41]([O-])=O)=[CH:36][N:35]=1>>[Cl:33][C:34]1[N:39]=[CH:38][C:37]2[N:41]([CH3:10])[C:6](=[O:8])[C@H:2]3[CH2:3][CH2:4][CH2:5][N:1]3[C:36]=2[N:35]=1
Reactant: CC[C@@H](N)C(=O)O
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CC[C@@H](N)C(=O)OC
Agent: COC(=O)C1CCCN1
Product: CN1C(=O)[C@H]2CCCN2c2nc(Cl)ncc21

Procedure:
Intermediate E was prepared in the same manner as intermediate B, using (R)-pyrrolidine-2-carboxylic acid as the starting material instead of (R)-2-aminobutanoic acid. No reductive amination step, such as that used for the conversion of compound II to compound III, was required. Rather, methylpyrrolidine-2-carboxylate was reacted directly with 2,4-dichloro-5-nitropyrimidine in the same manner as is described for the conversion of compound III to intermediate A. 1H NMR (CDCl3) δ: 7.65 (s, 1H), 4.19 (m, 1H), 3.81 (m, 1H), 3.68 (m, 1H), 3.32 (s, 3H), 2.51 (m, 1H), 2.08 (m, 3H).
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:18][OH:19]>CCO.CCOC(C)=O>[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)/[C:9](=[N:18]/[OH:19])/[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O/N=C1\CCOc2ccccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium acetate (503.852 mg, 6.14 mmol) was added to a stirred solution of 4-chromanone ([CAS491-37-2], 700 mg, 4.73 mmol) and hydroxylamine hydrochloride ([CAS5470-11-1], 426.808 mg, 6.14 mmol) in EtOH (31 mL). The mixture was stirred at 80° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc, and washed with water. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to yield I-36 (727.7 mg, 93%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:22]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Nc1ccncn1
Product: CN1C(C(=O)Nc2ccncn2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 86.5 %

Procedure:
Analogous to Example 45, 0.7 gm (2.1 millimols) of methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 0.24 gm (2.5 millimols) of 4-amino-pyrimidine were reacted, yielding 0.7 gm (86% of theory) of 2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(4-pyrimidinyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide; M.p.: 255° C. (decomposition).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH2:2]1.Cl.[NH2:15][C@@H:16]([C:18]1[C:23]([F:24])=[CH:22][C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:20]([CH3:30])[CH:19]=1)[CH3:17].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O1CCCC1>[F:24][C:23]1[CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:20]([CH3:30])=[CH:19][C:18]=1[C@H:16]([NH:15][C:11]([C:3]1[CH2:2][O:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13])[CH3:17]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: O=C(O)C1=Cc2ccccc2OC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)C2=Cc3ccccc3OC2)c(F)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 2H-chromene-3-carboxylic acid (0.015 g, 0.085 mmol), N-[4-((R)-1-aminoethyl)-5-fluoro-2-methylphenyl]methanesulfonamide hydrochloride (20.00 mg, 0.07 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.032 g, 0.085 mmol) in N,N-dimethylformamide (0.39 g) was added N,N-diisopropylethylamine (0.046 g, 0.35 mmol). Tetrahydrofuran (0.38 g) was added to dilute solution. The reaction was stirred overnight. It was then concentrated and purified by HPLC to obtain the product (10.8 mg, 37%) a solid. m/z=405.1 (M+1). 1H-NMR (400 MHz, DMSO-d) δ 9.19 (s, 1H), 8.61 (d, 1H, J=7.66 Hz), 7.37 (s, 1H), 7.30-7.21 (m, 3H), 7.07 (d, 1H, J=11.41 Hz), 6.96 (dt, 1H, J=7.54 Hz), 6.84 (d, 1H, J=7.81 Hz), 5.25-5.18 (m, 1H), 4.88 (s, 2H), 3.02 (s, 3H), 2.25 (s, 3H), 1.41 (d, 3H, J=7.07 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Zn]>[OH:21][C:19]([CH3:20])([CH:18]=[CH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:22][CH3:23])[CH:11]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
Using 1.19 g of 6-(p-benzyloxy-m-methoxyphenyl)-3-hexen-2-one, 0.64 ml of ethyl bromoacetate and 0.33 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 25 (a) affording 1.28 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-4-heptenoate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1
Reactant: CCCN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1
Reaction time: 15 h
Yield: 51.1 %

Procedure:
A mixture of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 17.4 mmol), palladium on carbon (0.4 g) and hydrochloric acid (0.5 ml, cone) in methanol (30 ml) was hydrogenated at 50 psi for 15 h under hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 4.7 g of crude product. Purification by flash column chromatography (Isooctane/ethylacetate, 1:1) gave the title compound (2.57 g, 51%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 258-260° C. MS m/z (relative intensity, 70 eV) 289 (M+, 4), 261 (16), 260 (bp), 177 (6) 70 (15).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C@H:14]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:15]([NH:17][C:18]2[S:19][C:20]([F:23])=[CH:21][N:22]=2)=[O:16])[CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].O>O1CCCC1.CO>[CH:33]1([S:30]([C:27]2[CH:26]=[CH:25][C:24]([C@@H:14]([CH2:13][C@H:10]3[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9]3)[C:15]([NH:17][C:18]3[S:19][C:20]([F:23])=[CH:21][N:22]=3)=[O:16])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1
Reactant: CC(=O)OCC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCN(C(=O)CO)C1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
2-((S)-3-((R)-2-(4-(Cyclopropylsulfonyl)phenyl)-3-((5-fluorothiazol-2-yl)amino)-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl acetate (47.0 mg, 89.8 μmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and thereafter, an aqueous solution of sodium hydroxide (2 M, 0.36 mL) was added to the obtained solution under ice-cold condition. The obtained mixture was stirred for 30 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (38.2 mg, 88%) in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH:22]2[CH:26]([CH2:27][CH3:28])[CH2:25][CH:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:36][C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>CO.CCOC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:27]([CH:26]1[CH:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[CH:36]2)[CH2:23][CH:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: CCC1CC(NS(=O)(=O)C2CC2)CC1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1CC(NS(=O)(=O)C2CC2)CC1n1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 65 °C
Yield: 100.1 %

Procedure:
To a solution of N-(3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.095 g, 75% purity, 0.142 mmol, prepared using L from Preparation #27 and Preparation #000.1 with DIEA, K.1 with TsCl and NaH, and BBB) and TMOF (0.016 mL, 0.147 mmol) in MeOH (3.09 mL) was added toluene-4-sulfonic acid hydrate (0.0003 g, 0.0015 mmol). The reaction was heated at about 65° C. for about 14 h. The reaction was cooled to ambient temperature and concd under reduced pressure to give a crude solid. The solid was dissolved in EtOAc (10 mL) and was washed with saturated aqueous NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic portion was separated and dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford N-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.075 g, 99%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.15 min; MS m/z: 514 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: O=CCc1ccccc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(CCc1ccccc1)CC2

Procedure:
The title compound (104 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and phenylacetaldehyde as in Example 35. MS (ESI): exact mass calculated for C24H28FN3, 377.23. found, m/z 378.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.27 (m, 9H), 4.39 (m, 1H), 3.88-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.56-3.52 (m, 3H), 3.45-3.20 (m, 3H), 3.17-3.14 (m, 2H), 2.89-2.84 (m, 2H), 1.41 (t, J=6.6 Hz, 6H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[O:12]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:7](=[CH:23][C:22]2[CH:25]=[CH:26][C:19]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=2)[S:1][C:2](=[S:3])[N:4]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)CN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S

Procedure:
To a solution of rhodanine-3-acetic acid (1.00 g) in acetonitrile (20 ml) were added 4-phenoxybenzaldehyde (1.14) and triethylamine (1.06 g), and the mixture was heated with reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to give [4-oxo-5-(4-phenoxybenzylidene)-2-thioxo-thiazolidin-3-yl]acetic acid (1.20 g).
Reaction SMILES: ClC[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.BrCC1C=CC([C:17]([O:19][CH2:20][CH3:21])=[O:18])=CC=1.[CH2:24]([NH:31][C:32]([C:34]1[S:38][C:37]([N:39]2[CH2:43][CH2:42]N[C:40]2=[O:44])=[N:36][C:35]=1[CH3:45])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:32]([C:34]1[S:38][C:37]([N:39]2[CH2:43][CH2:42][N:8]([CH2:7][C:6]3[CH:9]=[C:10]([CH:3]=[CH:4][CH:5]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:40]2=[O:44])=[N:36][C:35]=1[CH3:45])=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: N#Cc1ccc(CCl)cc1
Product: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Yield: 20 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with ethyl 4-(bromomethyl)benzoate to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: mp 118-120° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=8.3 Hz, 2H), 7.35-7.27 (m, 7H), 5.88 (t, J=5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 4.51 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 4.10-4.05 (m, 2H), 3.47-3.42 (m, 2H), 2.60 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 162.3, 157.1, 155.4, 153.1, 140.5, 137.9, 130.3, 130.1, 128.8, 128.1, 127.8, 127.6, 117.3, 61.1, 47.7, 44.0, 42.0, 41.8, 17.2, 14.3; MS (ES+) m/z 479.4 (M+1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:27])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[F:28].NC(N)=S>CCO.O>[F:28][C:7]1[CH:8]=[C:9]([C:12]([CH3:27])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:10]=[CH:11][C:6]=1[CH:2]=[O:1]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Agent: NC(N)=S
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Yield: 99.9 %

Procedure:
Di-tert-butyl [4-(1,3-dioxolan-2-yl)-3-fluorophenyl](methyl)malonate (0.91 g, 2.30 mmol) and thiourea (0.87 g, 11.4 mmol) were stirred in refluxing EtOH/H2O (6.7 mL/6.7 mL) for 7 hours. Room temperature was attained and the solvent removed in vacuo. H2O (100 mL) was added to the residue and the products extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 0.81 g of clean product (pale yellow gum, 100%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 1.8 Hz, 1H), 7.27 (dd, J=12.0, 1.8 Hz, 1H), 1.77 (s, 3H), 1.46 (s, 18H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]1[C:38]([CH3:43])=[N:39][O:40][C:41]=1[CH3:42]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][C:37]3[C:38]([CH3:43])=[N:39][O:40][C:41]=3[CH3:42])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=615.1 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloromethyl)-3,5-dimethylisoxazole.