Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of (RS)-5-(4-Benzyloxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 78 (0.86 g, 1.7 mmol) and NaOH solution (4 M, 0.85 mL, 3.4 mmol) in MeOH-THF (1:1, 6 mL) was stirred at room temperature overnight. The solvent was removed, and the residue diluted with water. The solution was washed with Et2O, acidified with 5% aqueous HCl, and extracted with EtOAc. The organic phase was then washed with brine, dried (Na2SO4) and the solvent removed under reduced pressure to afford 85 (0.81 g, 98%), m.p. 127.7-129.5° C. 1H NMR (DMSO-d6) δ 1.13-1.23 (m, 6H), 1.35-1.44 (m, 2H), 1.47-1.54 (m, 2H), 1.95-2.00 (m, 2H), 2.14-2.22 (m, 2H), 3.86 (br s, 1H), 5.02 (s, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.15-7.44 (m, 10H), 7.50 (br d, J=8.6 Hz, 1H), 12.01 (br s, 1H). 13C NM (DMSO-d6) δ 174.3, 171.7, 156.7, 142.3, 137.2, 131.1, 130.1, 128.4, 128.2, 127.8, 127.7, 125.6, 114.3, 49.3, 35.5, 35.2, 31.0, 30.5, 29.3, 28.5, 28.4, 25.3. ESMS 488 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:22]([Cl:23])[C:16]=2[O:15][CH2:14]1)[CH2:31][CH3:32])[CH3:29]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(CC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-ethylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 0.2), 98 (3), 87 (7), 86 (bp), 58 (6), 56 (3).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1>C(N(CC)CC)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([NH:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N#CCCN[C@H]1CCNC1
Solvent: CCN(CC)CC
Product: N#CCCN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 47.9 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (0.4 g), 3-[(3S)-3-pyrrolidinylamino]-propanenitrile (Example 87(a)) (0.3 g) and triethylamine (0.6 mL) were heated within a microwave in a sealed 10 mL vial for 60 minutes at 120° C. The volatiles were removed under vacuum and the mixture purified (SiO2, methanol:dichloromethane 1:99 as eluant) to give the sub-titled compound (0.25 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[S:27][CH:28]=[C:29]([C:31](OCC)=[O:32])[N:30]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]2[CH2:18][CH2:19][N:20]([S:23]([C:26]3[S:27][CH:28]=[C:29]([CH2:31][OH:32])[N:30]=3)(=[O:25])=[O:24])[CH2:21][CH2:22]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1csc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1cc(SC2CCN(S(=O)(=O)c3nc(CO)cs3)CC2)cc(C(C)(C)C)c1O

Procedure:
The title compound was prepared (116 mg, clear oil) in a manner similar to Ex. 5 from ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-thiazole-4-carboxylate (Ex. 19e) and LiAlH4. 1H-NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.23 (s, 2H), 5.31 (s, 1H), 4.84 (s, 2H), 3.80 (m, 2H), 2.90 (m, 2H), 2.42 (bs, 1H), 1.99 (m, 2H), 1.68 (m, 2H), 1.39 (s, 18H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:39]5[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reactant: OB(O)c1ccc(F)cc1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(F)cc5)ccc4C3=O)cc2F)C1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with 4-fluorophenylboronic acid by method O. The product with the molecular weight of 447.53 (C27H27F2N3O) was obtained in this way; MS (ESI): 448 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[C:15](O)(=[O:17])[CH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][C:6]1=[O:14]
Reactant: CC(=O)O
Reactant: O=c1oc2ccccc2n1CCCCl
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Temperature: 100 °C

Procedure:
A mixture of N-(3-chloropropyl)-2-benzoxazolinone (8.5 g, 40 mmol), polyphosphoric acid (100 g), and acetic acid (2.4 g, 2.3 ml, 40 mmol), was stirred and heated at 100° C. for 2 hours. The hot solution was poured into ice-water to deposit a yellow gum. The mixture was extracted with dichloromethane, and insolubles were filtered. The dichloromethane extract was washed with water, dried (K2CO3), and concentrated to afford 6.4 g of a slightly green solid. This was recrystallized from ethanol (95%) to yield N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone as a brown solid, 3.5 g, m.p.=100°-103° C.
Reaction SMILES: Cl[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CCCCCCC>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]#[N:22])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C(Cl)c2ccccc2)c1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cccc(C(C#N)c2ccccc2)c1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
A solution of 1-(chlorophenylmethyl)-3-methoxybenzene (5.5 g, 24 mmol) in DCM (100 mL) was cooled to 0° C. Trimethylsilyl cyanide (3.5 mL, 26 mmol) was added to the stirred solution. 1.0 M of tin tetrachloride in heptane (0.75 mL, 0.75 mmol) was then added. The solution was stirred for 2 hours, then quenched with MeOH (50 mL). The solvent was removed under reduced pressure. The crude material was then purified via silica gel chromatography to obtain the title compound (2.2 g, 10 mmol).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (87 mg, 81%), MS (ISP) m/z=429.4 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].O>C(Cl)Cl>[NH2:13][CH2:12][CH2:11][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NCCN
Solvent: O
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol, 1.0 eq) in CH2Cl2 (100 mL) was stirred at 0° C., ethane-1, 2-diamine (2.3 g, 38.24 mmol, 4 eq) was added drop-wise. Then, the mixture was stirred at 0° C. for 0.5 h. Water was added and extracted with EA (6×80 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to give N-(2-aminoethyl)-5-bromothiophene-2-sulfonamide (2.51 g, 92.0%). LC-MS (m/z)=284.1 [M+H]+.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[NH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc[nH]c12
Product: Clc1ncnc2cc[nH]c12
Yield: 36 %

Procedure:
Into a 50-mL round-bottom flask was placed a solution of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (5 g, 35.52 mmol, 1.00 equiv, 96%) in trichlorophosphate (20 mL). The resulting solution was stirred at reflux for 1 h, concentrated under vacuum, dissolved in 100 mL of ethyl acetate, washed with 2×100 mL of 10% aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:8) to afford 2 g (36%) of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.3 %

Procedure:
Treat a solution of cis/trans ethyl 4-hydroxycyclohexanecarboxylate (21.3 g, 0.124 mol) and imidazole (10.10 g, 0.148 mol) in DMF (150 mL) with t-butyl-diphenylsilyl chloride (37.39 g, 0.136 mol) and stir for 72 hours at room temperature. Dilute the reaction with diethyl ether and wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 40.4 g (80%) of the titled product. Rf=0.49 and 0.29 (5/1 hexanes/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCCCN(CC)CC1CCCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCN(CC)CC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(N-butyl-N-ethylaminomethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.23 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc2ccccc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with naphthalene-1-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(naphthalen-1-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O>>[OH:8][C:7]1[C:6]2[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][S:3][C:2]=2[N:1]=[CH:17][N:19]=1
Reactant: CCOC(=O)c1c(-c2ccco2)csc1N
Reactant: NC=O
Product: Oc1ncnc2scc(-c3ccco3)c12
Temperature: 200 °C
Yield: 52.5 %

Procedure:
A mixture of ethyl 2-amino-4-(2-furyl)thiophene-3-carboxylate (1.00 g, 4.21 mmol) and formamide (10.0 g, 0.2 mol) was warmed by microwave at 200° C. for 10 minutes. The mixture was concentrated in vacuo at 90° C., diluted with 40 mL of 10% methanol/dichloromethane, and filtered through a 40 gram silica gel column using 5% methanol/dichloromethane to wash the material through the column. The filtrate was again concentrated and the remaining residue was purified by column chromatography over silica gel using a gradient elution from 5 to 10% methanol in dichloromethane to give 0.482 g (52.4%) of 4-hydroxy-5-(2-furyl)thieno[2,3-d]pyrimidine as a brown solid.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].[Si]([O:35][CH2:36][CH:37]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[OH:35][CH2:36][CH2:37][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(CCO)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.083 g, 0.233 mmol) in MeOH (3 mL) and acetic acid (0.3 mL) was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.122 g, 0.699 mmol) and the reaction mixture was stirred at 70° C. overnight. NaBH3CN (0.073 g, 1.164 mmol) was added and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 26) to give (R)-6-{(R)-1-[1-(2-hydroxy-ethyl)-3-methyl-azetidin-3-yl]-ethyl}-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (0.0291 g, 31%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.04 (s, 1H), 6.84 (s, 1H), 4.81-4.78 (m, 1H), 4.62 (s, 2H), 4.15 (d, J=10.8 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.86 (d, J=10.8 Hz, 1H), 3.77-3.69 (m, 2H), 3.38 (m, 2H), 3.12-3.04 (m, 2H), 1.56 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.42-1.35 (m, 3H), 1.34-1.27 (m, 3H), 1.19-1.12 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.761 min.; MS m/z: 401 [M+H]+. SFC (Table 1, Method 28) Rt=5.52 min.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[H-].[Na+].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][C:32]=1[N+:39]([O-:41])=[O:40]>CN(C=O)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:33][C:32]=1[N+:39]([O-:41])=[O:40]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C=Cc2cccnc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Triphenylpyridin-3-ylmethylphosphonium chloride (1.95 g) was added into an ice-cooled DMF suspension (40 ml) containing sodium hydride (60% in oil) (0.26 g), followed by 30 minutes of stirring at room temperature. The reaction solution was cooled to 0° C. and 4-chloro-3-nitrobenzaldehyde (1.04 g) was added portionwise thereto, followed by 2 hours of stirring at room temperature. To the residue formed by evaporating the reaction solution under reduced pressure was poured an appropriate amount of purified water, followed by extraction with ethyl acetate. Thereafter, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by solvent evaporation was purified by silica gel column chromatography to obtain 3-[2-(4-chloro-3-nitrophenyl)vinyl]pyridine (0.86 g) from the fractions eluted with ethyl acetate-hexane (2:1 (v/v)).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([O:13][C:15](=[O:17])[CH3:16])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 22 °C
Reaction time: 10 h
Yield: 79.4 %

Procedure:
To a stirred solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6e, 13.5 g, 67 mmol), TEA (81 g, 804 mmol), DMAP (1.6 g, 13 mmol) in anhydrous DCM (150 mL) was added acetic anhydride (62 g, 603 mmol). After being stirred at 22° C. for 10 hours, the reaction was quenched by the saturated NaHCO3 solution. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 EtOAc in petroleum ether) to afford 13 g of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl]acetate (compound 6f) as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:15]([CH3:26])[NH:14][C:13]=1[CH:27]=O>N1CCCC1.C(O)C>[CH3:11][C:12]1[C:16]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[C:15]([CH3:26])[NH:14][C:13]=1[CH:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCCN1CCOCC1
Temperature: 90 °C
Yield: 84.5 %

Procedure:
A mixture of 1,3-dihydroindol-2-one (133 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carboxaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 308.9 mg (85%) of 3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a yellow solid:
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:37](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([OH:32])=[S:37])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise in succession to a solution, cooled to -10°, of 2.82 g (10 mmol) of 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour and subsequently a strong current of hydrogen sulphide is passed through for a period of 2 hours. After acidifying with 2N sulphuric acid, the organic phase is separated, dried and concentrated in vacuo. The 4-p-nitrobenzyloxycarbonylaminothiobutyric acid obtained can be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([O:31][CH3:32])[CH:24]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:33])[CH3:21])=[CH:24][C:25]=3[O:31][CH3:32])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N(C)C)ccc1C=O
Product: COc1cc(N(C)C)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 42.6 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-dimethylamino-2-methoxy-benzaldehyde (23.3 mg, 0.130 mmol) were reacted to produce 25 mg (43%) of the title compound. mp: 218-220° C., 1H NMR (300 MHz, DMSO-d6): 13.00 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 6.99 (d, J=8 Hz, 2H), 6.43 (br s, 1H), 6.33 (br s, 1H), 5.16 (t, J=8 Hz, 1H), 3.94 (s, 3H), 2.87 (s, 1H), 2.73 (s, 1H), 2.59 (d, J=7 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.90 (s, 1H), 1.37 (d, J=8 Hz, 1H). MS: 497, 499 (M+H), HPLC: 2.65 min (G method).