Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: C1=COCCC1
Reactant: N#Cc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
3-(Hydroxymethyl)benzonitrile (5.00 g; 37.6 mmoles) and 3,4-Dihydro-2H-pyran (3.77 mL; 41.4 mmoles) were dissolved in methylene chloride (25 mL) under nitrogen and the solution was cooled to 5° C. p-Toluenesulfonic acid monohydrate (74 mg; 0.37 mmoles) was added and the mixture was stirred for 2 hours at 25° C. The reaction mixture was diluted with methylene chloride (25 mL). The solution was washed with aqueous sodium bicarbonate solution (30 mL) and aqueous sodium chloride solution (30 mL). The solution was dried over sodium sulfate and filtered. The solvent was removed under vacuum to give the product, 3-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzo-nitrile (7.34 g; 89%) as an oil. 1H NMR (400 MHz) CDCl3 δ 7.68-7.70 (1H, m), 7.54-7.61 (2H, m), 7.42-7.48 (1H, m), 4.82 (1H, d, J=12.5 Hz), 4.72 (1H, t, J=3.3 Hz), 4.53 (1H, d, J=12.5 Hz), 3.84-3.92 (1H, m), 3.53-3.60 (1H, m), 1.60-1.95 (6H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[CH:12][N:13]=2)[N:10]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15].[C:26]1([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[C:39]1([CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:33]2[CH2:34][CH2:35][NH:36][CH:37]([C:14]([O:1][CH2:2][CH2:3][O:4][C:5]3[CH:6]=[CH:7][C:8]4[N:9]([N:11]=[CH:12][N:13]=4)[N:10]=3)=[O:15])[CH2:38]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCOc1ccc2ncnn2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCOc1ccc2ncnn2n1)C1CN(C(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
6-(2-Hydroxyethoxy)[1,2,4]triazolo[1,5-b]pyridazine (450 mg) was dissolved in tetrahydrofuran (20 ml), followed by addition of carbonyldiimidazole (649 mg). The mixture was stirred at room temperature for 3 hours, followed by addition of 1-(diphenylmethyl)piperazine (1.07 g) and N-ethyldiisopropylamine (0.73 ml). The mixture was stirred at 60° C. for 17 hours and concentrated under reduced pressure. Ice-water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with a mixture of ethyl acetate and hexane (1:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were recrystalized from ethyl acetate to yield the title compound (464 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C

Procedure:
A solution of 11.5 g. (0.07 mol.) of 3-methyl-4-methoxybenzoic acid and 10.7 g. (0.09 mol.) of thionyl chloride in 60 ml. of methylene chloride is refluxed on a steam bath for 2 hours. Concentration under reduced pressure and distillation of the residue gives 3-methyl-4-methoxybenzoic acid chloride, m.p. 37°-39°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6](C=O)=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CN.[C:28]([BH3-])#[N:29].[Na+].[C:32]([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:18]=2[CH2:32][NH:29][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2)c1C=O
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.228 g, 0.65 mmol) and methylamine (2M in THF; 0.5 mL, 0.84 mmol) in CH2Cl2 (3.4 mL) was added sodium cyanoborohydride (0.061 g, 0.97 mmol), followed by acetic acid (1 drop). The reaction was stirred at room temperature overnight, until no starting material was seen by analytical LCMS. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[CH:55](/B(O)O)=[CH:56]\[CH3:57]>>[CH2:33]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[C:30]([C:25]1[C:26]([Cl:29])=[C:27]([CH3:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[NH:14][S:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH2:53][CH3:54])=[CH:3][C:2]=3/[CH:55]=[CH:56]/[CH3:57])(=[O:13])=[O:12])=[CH:18][C:19]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:24]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: C/C=C/B(O)O
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3Br)CCN4CC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: C/C=C/c1cc2c(cc1S(=O)(=O)NC(=O)c1ccc(-n3nc(C(=O)N(CCCC)CCCC)c(Cl)c3C)c(C(=O)N3CCc4ccccc4C3)c1)N(CC)CC2
Yield: 23.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 87, 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 35 mg, 0.042 mmol) and (E)-prop-1-enylboronic acid (14 mg, 0.17 mmol) were converted to the title compound (8 mg, 22%) as a white solid. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.03-7.99 (m, 1H), 7.88-7.87 (m, 1H), 7.72-7.67 (m, 1H), 7.31-7.12 (m, 6.5H), 6.94-6.93 (m, 0.5H), 6.05-5.90 (m, 1H), 4.75-4.40 (m, 2H), 3.95-3.55 (m, 1H), 3.47 (t, J=8.4 Hz, 2H), 3.27-3.15 (m, 2H), 3.26 (q, J=7.0 Hz, 2H), 3.01 (t, J=7.9 Hz, 2H), 2.80-2.60 (m, 2H), 2.34 (s, 2H), 2.30 (s, 1H), 2.09-2.07 (m, 1H), 1.85-1.83 (m, 2H), 1.55-0.90 (m, 14H), 0.95-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.70 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 799.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73]([CH:75]3[CH2:78][CH2:77][CH2:76]3)=[O:74])[C@@H:69]([OH:79])[C@H:68]2[OH:80])=[C:60]([NH:81][CH2:82][CH:83]([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[N:59]=1.[CH2:96]([N:103]1[CH2:107][CH2:106][C@@H:105]([NH2:108])[CH2:104]1)[C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:96]([N:103]1[CH2:107][CH2:106][C@@H:105]([NH:108][C:58]2[N:66]=[C:65]3[C:61]([N:62]=[CH:63][N:64]3[C@@H:67]3[CH2:71][C@H:70]([NH:72][C:73]([CH:75]4[CH2:78][CH2:77][CH2:76]4)=[O:74])[C@@H:69]([OH:79])[C@H:68]3[OH:80])=[C:60]([NH:81][CH2:82][CH:83]([C:84]3[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=3)[C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)[N:59]=2)[CH2:104]1)[C:97]1[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@@H]4CCN(Cc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O)C1CCC1

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide (Intermediate K) and by replacing (3R)-3-aminopyrrolidine with (R)-1-benzyl-pyrrolidin-3-ylamine. (MH+ 687.5)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2OC(=O)[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:16]>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C#N
Reactant: O=c1oc(/C=C/c2ccccc2)ns1
Product: CCOC(=O)c1nc(/C=C/c2ccccc2)ns1
Yield: 65.9 %

Procedure:
5-[(E)-2-Phenylethenyl]-1,3,4-oxathiazol-2-one (1.4 g, 7.0 mmol) was mixed with ethyl cyanoformate (2.4 g, 25 mmol) in xylenes, and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo, and the resulting material was recrystallized from ethyl acetate-ethanol (1:1) to give ethyl 3-[(E)-2-phenylethenyl]-1,2,4-thiadiazole-5-carboxylate (1.2 g, 66% yield) as a light yellow solid. M.p. 79–80° C. 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=16 Hz, 1H), 7.61 (m, 2H), 7.40 (m, 3H), 7.29 (d, J=11 Hz, 1H), 4.56 (q, J=7 Hz, 2H), 1.50 (t, J=7 Hz, 3H). MS (EI ionization) 259 (M+−H).
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1)(=O)[CH3:2].[Cl-].[NH4+:15].[C-:16]#[N:17].[Na+]>N.CO>[NH2:15][C:1]([C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1)([C:16]#[N:17])[CH3:2]
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(C(C)(N)C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 1-acetyl-1-cyclopropanecarboxylate (9.21 g, 50.0 mmol) was dissolved in a 7N solution of ammonia in methanol (300 mL), and to this solution in an ice bath were added concentrated ammonia solution (90 mL), ammonium chloride (53.5 g, 1.00 mol), and sodium cyanide (4.90 g, 100.0 mmol). The mixture was stirred at room temperature for 18 hours, and the solvent was concentrated under reduced pressure. To the concentrate was added water (100 mL), and the solution was extracted with dichloromethane (300 mL+2×100 mL). The organic layers were combined, and dried by adding anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure to obtain 10.15 g (48.3 mmol, 97%) of the crude target compound as a pale brown oil. The thus obtained crude product was used in the subsequent reaction with no further purification.
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)CCCCCCCCC.Br[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2>O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCBr
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2cc(OC)ccc2c1

Procedure:
A THF solution of n-decyl magnesium bromide (prepared as a THF (2 ml) solution of n-decyl bromide (2.2 ml, 11 mmol) and Mg (292 mg, 12 mmol)) was added to 6-bromo-2-methoxynaphthalene (2.37 g, 10 mmol) easily available from a reagent manufacturer and a THF (10 ml) solution of Ni(dppp)Cl2 (271 mg, 0.5 mmol), and the mixture was heated under reflux for 19 hours. After cooling, the mixed solution was diluted with water (10 ml), and non-reacted Mg was filtered out. The filtered solution was extracted with ether (5 ml×3). The extracted organic phases were collected (10 ml×3), and dried with MgSO4, and condensed with an evaporator. The condensed organic phase was recrystallized with hexane to obtain 6-n-decyl-2-methoxynaphthalene (compound (3)-64) as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[N:10][CH:11]=2.CCN(C(C)C)C(C)C.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:13]=[C:5]1[C:6]2[C:7](=[N:8][CH:9]=[N:10][CH:11]=2)[N:12]=[C:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:4]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NCc1nc2ncncc2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)NCc1nc2ncncc2c(=O)[nH]1
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a suspension of 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (12 mg, 0.068 mmol) in THF (0.2 mL) and DIPEA (0.050 mL, 0.29 mmol) was added 3-phenyl-propionyl chloride (14 mg, 0.08 mmol) at ambient temperature. The reaction mixture was stirred one hour, evaporated and purified by column chromatography (silica gel, EtOAc/MeOH, 1/1) to yield N-(4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide as a white solid (0.8 mg, 3.8%). MS (m/e): 310.3 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C=O.[C:12]([BH3-])#N.[Na+].O>C1COCC1>[CH3:12][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCN1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(CCO)CC1
Temperature: 50 °C

Procedure:
In THF (30 ml) were added N-(2-hydroxyethyl)piperazine (500 mg, 3.84 mmol), a solution of formaldehyde (3117 mg, 38.41 mmol) and sodium cyanoborohydride (1207 mg, 19.20 mmol). The mixture was heated up to 50° C. overnight under stirring. After cooling some water was added and the mixture was extracted with DCM (3×). The organic layers were dried over MgSO4 and evaporated. The residue was purified over a silica plug with DCM/MeOH 9:1 as eluant to afford an oil (370 mg, Y=67%). 1H NMR (DMSO-d6) δ 4.45 (t, J=5.3 Hz, 1H), 3.51-3.45 (m, 2H), 3.02-2.84 (m, 4H), 2.71-2.64 (m, 2H), 2.61 (s, 3H), 2.58-2.53 (m, 2H), 2.47-2.43 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][CH2:13]Cl)=[O:11].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1>C(O)C>[CH3:15][C:16]1[N:20]([CH2:13][CH2:12][C:10](=[O:11])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: CC1=NCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Solvent: CCO
Product: CC1=NCCN1CCC(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Ex. IA react 5.29 gm. (0.025 M) of 3-chloro-2',6'-propionoxylidide with 10.53 gm. (0.125 M) of lysidine in 200 ml. of anhydrous ethanol to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C.Cl.C(OC([N:13]1[CH2:18][C@@H:17]([CH3:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:66])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[N:41]=[C:42]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[NH:43][CH:44]=5)=[CH:36][CH:35]=4)=[C:30]([O:61][C:62]([F:65])([F:64])[F:63])[CH:29]=3)=[CH:22][N:21]=2)[CH2:15][C@@H:14]1[CH3:67])=O)(C)(C)C>C(O)C>[CH3:59][O:58][C:56](=[O:57])[NH:55][C@H:51]([C:50]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:42]1[NH:43][CH:44]=[C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][C:28]([NH:27][C:26]([C:23]4[CH:22]=[N:21][C:20]([N:16]5[CH2:15][C@H:14]([CH3:67])[NH:13][CH2:18][C@H:17]5[CH3:19])=[CH:25][CH:24]=4)=[O:66])=[CH:29][C:30]=3[O:61][C:62]([F:65])([F:63])[F:64])=[CH:35][CH:36]=2)[N:41]=1)=[O:60])[CH:52]([CH3:53])[CH3:54]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (63.2 mL, 888 mmol) was added to ethanol (360 mL) and stirred at RT for 1 h. To the resulting HCl solution was added a solution of (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (73 g, 84 mmol) in ethanol (360 mL). The reaction mixture was stirred at RT overnight.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1N.N(OCCC(C)C)=O.[CH3:19][S:20]SC>>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[S:20][CH3:19]
Reactant: Nc1c(F)cc(F)cc1Br
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1c(F)cc(F)cc1Br
Temperature: 75 °C
Yield: 66 %

Procedure:
Dissolve 2-bromo-4,6-difluoroaniline (40 g, 192 mmol) in methyldisulfide (250 mL) and heat to 75° C. under nitrogen. Add isoamyl nitrite (67 mL, 500 mmol) dropwise via an addition funnel trough a reflux condenser (˜1 drop/sec). Large exotherm may occur if addition is too fast. After addition is complete, heat the reaction to 95° C. for 1 hour and cool to room temperature and concentrate in vacuo. Purify dark brown residue via silica gel chromatography eluting with hexanes to yield 30.3 g of 1-bromo-3,5-difluoro-2-methylsulfanyl-benzene (66%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[NH2:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:14]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:9]2[CH2:10][CH2:11][O:12][CH3:13]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCNc1nc(C)nc(Cl)c1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCn1c(-c2ccccc2Cl)nc2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
Heat a solution of 6-chloro-N4-(2-methoxyethyl)-2-methylpyrimidine-4,5-diamine (5.0 g, 0.023 mol), 2-chlorobenzaldehyde (4.8 g, 0.03 mol), 15% FeCl3 on SiO2 (20 g) in 1,4-dioxane (150 mL) to 100° C. for 16 h. Remove the silica by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (150 mL) and add DDQ (5.2 g, 0.022 mol) at 0° C., and stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with ethyl acetate:n-hexane (40:60) to give the title compound (2.9 g). ES/MS m/z 337 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:21]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C(#N)C>[Br:21][C:11]1[CH:12]=[N:13][N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]=1[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(-c2c(Br)cnn2C2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (10 g, 34.8 mmol) and acetonitrile (120 ml) were added into a flask and the temperature was adjusted to 0° C. with an ice bath. N-bromosuccinimide (6.80 g, 38.2 mmol) was added in small batches keeping the temperature below 5° C. The mixture was stirred at room temperature for 3 h. 10% NaHSO3 (100 ml) was added and the mixture was stirred for 15 min. The reaction mixture was extracted with DCM. The combined organic phases were dried, filtered and evaporated. The product was purified by recrystallization from ethanol. Yield 82%. 1H-NMR (400 MHz; DMSO-d6): δ 1.51-1.59 (m, 2H), 1.62-1.76 (m, 1H), 1.90-2.00 (m, 2H), 2.06-2.18 (m, 1H), 3.62-3.70 (m, 1H), 3.91-3.98 (m, 1H), 5.49 (dd, 1H), 8.02 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([P:17]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.C(O)CO>[Ni](Cl)Cl.O>[Br-:1].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([P+:17]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[CH:19][CH:20]=1
Reactant: Oc1ccccc1Br
Reactant: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Cl[Ni]Cl
Solvent: OCCO
Solvent: O
Product: COc1ccc([P+](c2ccc(OC)cc2)(c2ccc(OC)cc2)c2ccccc2O)cc1
Product: [Br-]
Temperature: 160 °C

Procedure:
10.4 g (0.060 mol) of 2-bromophenol, 23.20 g (0.066 mol) of tris(4-methoxyphenyl) phosphine, 0.65 g (5 mmol) of nickel chloride, and 40 ml of ethylene glycol were put into a separable flask (volume, 200 ml) equipped with a condenser and a stirrer, and reacted with stirring under heat at 160° C. The reaction liquid was cooled, 40 ml of pure water was dropwise added thereto, and the deposited crystal was washed with toluene, taken out through filtration, and dried to obtain tris(4-methoxyphenyl)(2-hydroxyphenyl)phosphonium bromide.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Si:12]([O:19][CH:20]1[CH2:37][N:25]2[C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[CH:28][C:27]=3[N:36]=[C:24]2[CH2:23][N:22]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(Cl)(Cl)Cl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:61]>>[NH2:61][C:28]1[C:27]2[N:36]=[C:24]3[CH2:23][N:22]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:21][CH:20]([O:19][Si:12]([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14])[CH2:37][N:25]3[C:26]=2[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc3cnc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2nc3c(N)nc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
mCPBA (3.89 g of 77% pure material, 17.36 mmol) was added to a solution of tert-butyl 11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (4.07 g, 8.68 mol chloroform, and the reaction was stirred for 30 minutes at ambient temperature. Additional mCPBA (0.5 equivalent) was added, and the reaction was stirred for four hours. Ammonium hydroxide (50 mL) was added with vigorous stirring, and after ten minutes, p-toluenesulfonyl chloride (1.82 g, 9.55 mmol) was added. The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 98.5:1:0.5 and 89:10:1 dichloromethane:methanol:ammonium hydroxide), and the resulting product was dried under high vacuum to provide 2.25 g of tert-butyl 6-amino-11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.