Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3].[NH2:15][C:16]1([O:36][CH3:37])[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH2:28][S:29][C:30]1[S:31][C:32]([CH3:35])=[N:33][N:34]=1)=[C:21]2[C:25]([OH:27])=[O:26]>>[N:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:15][C:16]2([O:36][CH3:37])[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28][S:29][C:30]2[S:31][C:32]([CH3:35])=[N:33][N:34]=2)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(CC(=O)O)ccc1O
Reactant: COC1(N)C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CSC21
Product: COC1(NC(=O)Cc2ccc(O)c(N=[N+]=[N-])c2)C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CSC21

Procedure:
The title compound is prepared when 3-azido-4-hydroxybenzeneacetic acid is reacted with 7-amino-7-methoxy-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid according to Procedure V.
Reaction SMILES: C[O-:2].[Na+].C([C:7]1[CH:19]=[CH:18][C:10]2[C:11](=[O:17])[C:12]([Br:16])=[C:13]([CH3:15])[O:14][C:9]=2[CH:8]=1)(=O)C.Cl>CO>[Br:16][C:12]1[C:11](=[O:17])[C:10]2[CH:18]=[CH:19][C:7]([OH:2])=[CH:8][C:9]=2[O:14][C:13]=1[CH3:15]
Reactant: CC(=O)c1ccc2c(=O)c(Br)c(C)oc2c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1oc2cc(O)ccc2c(=O)c1Br
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2.2 ml of sodium methylate (8% of Na (w/v) in methanol) are added under an inert atmosphere to a suspension of 2.3 g (7.7.10-3 mol) of 7-acetyl-3-bromo-2-methyl-4H-1-benzopyran-4-one in 40 ml of methanol. After 30 minutes, the reaction mixture is hydrolyzed with an iced solution of hydrochloric acid. The precipitate formed is filtered off and then washed until the pH of the washings is neutral. 1.9 g (yield: 96%) of the expected product are thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]3[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:16]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)OC)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.281 g, 0.543 mmol) was reacted with 1N KOH (1.1 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.177 g, 0.351 mmol, 65%) as a white solid, mp 141-143° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=6.7 Hz, 3H), 1.13-1.22 (m, 4H), 1.53-1.59 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 4.69 (s, 2H), 5.27 (s, 2H), 6.84 (d, J=7.5 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.20 (t, J=7.0 Hz, 2H), 7.33-7.38 (m, 4H), 7.43 (t, J=7.2 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.75 (s, 1H), 13.00 (broad s, 1H); IR (solid) 3030, 2910, 2860, 1750, 1605, 1520, 1470, 1440, and 1230 cm−1; [ESI(−)], m/z 503 (M−H)−; Anal. Calcd. for C34H33NO3.0.25H2O: C, 80.37; H, 6.64; N, 2.76; Found: C, 80.55, H, 6.58; N, 2.70.
Reaction SMILES: [OH:1][CH:2]([C:18](=[O:58])[N:19]([CH:31]([CH3:57])[CH:32]([C:48]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=1)[CH2:33][C:34]1[O:35][C:36]([C:39](=[O:47])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:38]=1)[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH:3]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5][C:6]([O:8]C(C)C)=[O:7].C(OC(C(=C(O)C(=O)N(C(C)C(C1C=CC([N+]([O-])=O)=CC=1)CC1OC(C(=O)NC2C=CC=CC=2)=CC=1)CC1C=CC2C(=CC=CC=2)C=1)CC(O)=O)=O)(C)(C)C>>[OH:1][C:2]([C:18](=[O:58])[N:19]([CH:31]([CH3:57])[CH:32]([C:48]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=1)[CH2:33][C:34]1[O:35][C:36]([C:39](=[O:47])[NH:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:38]=1)[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[C:3]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Agent: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1)N(Cc1ccc2ccccc2c1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Product: CC(C)OC(=O)C(CCC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1

Procedure:
Isopropyl 5-hydroxy-4-isopropoxycarbonyl-5-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]pentanoate was treated in the same manner as in Example 25(2) and (3) to obtain the above-identified compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: c1cncc(-c2cc3c(s2)-c2ccccc2OCC3)c1

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 3-pyridine boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica gave 152. 1H NMR (400 MHz, CDCl3): 3.29 (2H, t), 4.39 (2H, t), 7.05-7.10 (2H, m), 7.18-7.22 (2H, m), 7.32-7.35 (1H, m), 7.74 (1H, dd), 7.89 (1H, dt), 8.55 (1H, dd), 8.91 (1H, s). MS: (ESI+) 280
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)C.Cl.[CH3:27][C:28]1[O:29][C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:35]=2[N:36]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=[C:6]2[CH2:5][C:4]([N:32]2[CH2:33][CH2:34][C:35]3[N:36]=[C:28]([CH3:27])[O:29][C:30]=3[CH2:31]2)=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Reactant: Cc1nc2c(o1)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc2c(o1)CN(C(=O)Cc1nc(-c3ccc(F)cc3)cn1-c1ccc(F)cc1)CC2
Yield: 19.1 %

Procedure:
70 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester, 55 mg 2-methyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine hydrochloride and 0.1 mL DIPEA in 2 mL NMP was stirred 50 min at 180° C. under microwave condition. The reaction was poured into water and extracted with EtOAC. The organic layer was dried with magnesium sulfate and evaporated the residue was purified by HPLC (Waters Symmetry 50×140 mm water+0,3% HCOOH/methanoll 10% until 90% in 14 min) to yield 17 mg desired product. Rt: 1.10 (method A), (M+H)+: 435
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](O)[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19]([O:21]C=C)[CH3:20]>>[CH:19]([O:21][CH2:15][CH:14]=[C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[CH2:20]
Reactant: CC(O)=C1CCN(Cc2ccccc2)CC1
Reactant: C=COCC
Agent: [Na+]
Agent: [OH-]
Product: C=COCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.08 g of (1-benzylpiperidin-4-ylidene)ethanol in vinyl ethyl ether (30 ml) was added in a nitrogen atmosphere 0.107 g of mercurous trifluoroacetate. After stirring at room temperature for 18 hours, 10 ml of a 10% aqueous solution of sodium hydroxide was added thereto and the resulting mixture was extracted with n-hexane (50 ml). The organic layer was washed with an aqueous solution of sodium chloride (3×10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to thereby give 1.153 g of the title compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 49 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3,4-dichloro-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 25 mg (45%) of the title compound. LC/MS (m/z): 510 (M+1)+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>CC(C)=O.CCOCC>[C:20]([O:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CC(=O)Oc1ccc(C)cc1-n1nc2ccccc2n1
Yield: 67.7 %

Procedure:
Into a flask provided with a magnetic stirrer is added 10.0 g of 2-(2H-benzotriazol-2-yl)-4-methylphenol dissolved in 350 ml acetone. Then 10% NaOH is added dropwise until the pH is 9. With stirring, 4.1 g of acryloyl chloride is added dropwise while maintaining the pH between 7 and 9 by addition of dilute base. After the addition is complete, the solvent is evaporated leaving a yellow residue which is dissolved in 80 ml ether and extracted with an equal volume of 5% NaOH solution until the aqueous washings are colorless. After evaporation of the ether, there is left 8.4 g of a yellow residue as the product, whose structure, is confirmed by NMR. The yield is 67.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=N1.N1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([N:37]5[CH2:38][CH2:43][CH2:42][CH2:41]5)=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: O=C([C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine. Melting point: 206°-209° C.; Rf : 0.52 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][N:8]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Solvent: CCNCC
Solvent: CCO
Product: CCN(CC)CCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 135.8 %

Procedure:
20 mg of 4-(benzylamino)-6-({4-[4-(2-methylsulfonyloxyethyl)piperidino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 58) was dissolved in 1 mL of ethanol, to which 0.5 mL of diethylamine was added, and stirred in a sealed tube at 100° C. for 3 hours. After cooling, the solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 13 mg (68%) of the title compound as a slight brown crystalline powder.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>C(O)C>[OH:2][N:1]=[C:8]([NH2:9])[C:7]1[CH:10]=[CH:11][C:4]([CH3:3])=[N:5][CH:6]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: NO
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cn1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 0.765 g, 10 mmol) in ethanol (10 mL) was treated with a solution 6-methylnicotinonitrile (Aldrich, 12.8 g, 100 mmol) in ethanol (10 mL). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3 H), 6.02 (bs, 2 H), 7.59 (m, 1 H), 8.06-8.0 (m, 2 H), 10.2 (s, 1 H) ppm; MS (DCI/NH3) m/z 152 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH:19][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Reactant: COc1ccc([N+](=O)[O-])cc1N
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Temperature: 150 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 1 and 16.8 g of 2-methoxy-5-nitroaniline was stirred in an oil bath at 150° C for four hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from acetonitrile to obtain 29 g (yield 85%) of Coupler (7) having a melting point of 138° to 140° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:36]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[O:42])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5 g, 5.49 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (1.66 g, 7.14 mmol) and HOAc (329 mg, 5.49 mmol) in DCE (40 mL) was added NaB(OAc)3H (2.33 g, 11 mmol) in one portion. Then the resulting reaction mixture was stirred at rt overnight. Saturated aqueous NaHCO3 (40 mL) was added to quench the reaction, then was extracted with DCM (50 mL×3), dried over anhydrous Na2SO4 and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 50:1) to afford the desired compound (2.3 g, yield: 64%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.14 (d, J=2.5 Hz, 1H), 7.35-7.28 (m, 5H), 7.20 (d, J=4.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.40-5.39 (m, 1H), 5.08-5.07 (m, 2H), 4.96-4.94 (m, 1H), 4.64 (s, 2H), 4.26-4.24 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.10-3.05 (m, 0.55H), 2.86-2.82 (m, 2H), 2.26-2.20 (m, 3H), 2.10-1.59 (m, 5H), 1.58 (s, 3H), 1.37 (s, 3H), 1.35-1.25 (m, 0.6H), 1.15-1.08 (m, 0.5H) ppm; LC-MS (m/z): 672.4 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[Cl:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: CC(C)c1ccc(Cl)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cl)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-1-chloro-4-isopropylbenzene (0.37 g, 1-59 mmol) in dry THF (5 mL) at −78° C., n-butyl lithium (0.76 mL, 1.90 mmol, 2.5 M) was added. The solution was stirred at −78° C. for 30 min. Trimethyl borate (0.53 mL, 4.76 mmol) was added. The solution was stirred at −78° C. for 2.5 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over Na2SO4. The residue was used without further purification after evaporation of the solvent.
Reaction SMILES: [Na+:1].[Na+].[Na+].C[S:5][CH:6]([CH:10]([S:14]([OH:17])(=[O:16])=[O:15])[C:11]([O-:13])=[O:12])[C:7]([O-:9])=[O:8]>>[SH:5][CH:6]([CH:10]([S:14]([OH:17])(=[O:16])=[O:15])[C:11]([O-:13])=[O:12])[C:7]([O-:9])=[O:8].[Na+:1].[Na+:1].[Na+:1]
Reactant: CSC(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Agent: [Na+]
Product: O=C([O-])C(S)C(C(=O)[O-])S(=O)(=O)O

Procedure:
trisodium ⊕-methylthio-β-sulfosuccinate
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:49][C:50]1[C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=[C:52]([Cl:62])[CH:51]=1.ClCCl.C(O)C.N.ClCl>CN(C)C=O>[NH2:49][C:50]1[C:55]2[NH:56][C:57]([C@@H:59]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:60])=[N:58][C:54]=2[CH:53]=[C:52]([Cl:62])[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: C[C@H](N)c1nc2cc(Cl)cc(N)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)cc(N)c3[nH]2)ccc1C(=O)N1CCCC1
Yield: 22 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(7-amino-5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 22%; Rf value: 0.45 (silica gel; dichloromethane/ethanol/ammonia=9:1:0.1); C22H24ClN5O2 (425.92); mass spectrum: (M+H)+=426/428 (chlorine isotope).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH2:27][CH3:28])[C:24]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CCC(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 371 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.91 (m, 1H), 2.19 (m, 1H), 4.38 (m, 2H), 7.38 (d, J 8.5, 2H), 7.64 (d, J 8.5, 2H), 7.96 (t, J 7.8, 1H), 8.20 (d, J 7.1, 1H), 8.39 (d, J 8.1, 1H), 8.72 (s, 1H), 9.02 (t, J 6.8, 1H), 9.81 (s, 1H), 10.12 (br s, 1H); Anal. Calcd for C21H19F3N2O: C, 67.73; H, 5.14; N, 7.52. Found: C, 67.46; H, 4.90; N, 7.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[C:19]([CH2:26][C:27](O)=O)[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:27][CH2:26][C:19]1[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=13)[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(O)Cc1cnn2ccccc12
Product: CCCN(CCc1cnn2ccccc12)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 3-pyrazolo[1,5-a]pyridinyl acetic acid (A3-13: R=OMe, Cy=3-pyrazolo[1,5-a]pyridinyl) (synthesis according to literature: Gmeiner, P. Arch Pharm 1988, Vol 321, p 517) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O.[ClH:18]>C(OCC)(=O)C>[ClH:18].[CH3:1][O:2][C:3](=[O:17])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CCCN1

Procedure:
(R)-1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl-acetic acid methyl ester (5.0 g, 20.6 mmol), prepared as described in EXAMPLE 1A, is treated with ethyl acetate saturated with HCl gas to give (R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid (3.62 g, 20.3 mmol) which is used directly in the next step. This material (4.69 g, 26.3 mmol) is treated with THF (85 mL) and a 1 M solution of lithium bis(trimethylsilyl)amide in THF (52.5 mL, 52.5 mmol) at −15° C. under nitrogen. After stirring 10 min at −15° C. a solution of 3-bromomethyl-benzonitrile (4.63 g, 23.8 mmol) in THF (30 mL) is added dropwise. The reaction mixture is stirred at −15° C. for an additional 30 min and then warmed to −5° C. for 30 min. The reaction is quenched with methanol and concentrated to dryness. The residue is taken up in methylene chloride and extracted with saturated bicarbonate (250 mL). The aqueous layer is washed with methylene chloride (2×); the organic layers are combined and washed with water, dried over sodium sulfate and concentrated to give the title compound as an amber oil (5.82 g, 22 mmol).