Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(O)=O>CCO>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([NH:1][NH:2]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/NNc1cc(C#N)ccn1
Yield: 34.6 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH >8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233. Found, 233.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Product: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1

Procedure:
A mixture of 9.9 g (32.6 mmol) of (3-acetylphenyl)diphenyl phosphane and 7.7 g (64.7 mmol) of N,N-dimethylformamide dimethylacetal is refluxed under cover gas for 2 h. After removal of the volatiles in high vacuum, the product crystallizes at room temperature. The orange solid is washed with diethyl ether. (Purity: >95%)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)([CH3:33])[CH3:31]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87.0 mg, 0.214 mmol) and propan-2-amine (18.93 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (39.6 mg, 0.088 mmol, 41.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6H) 1.85-2.00 (m, 3H) 2.11-2.24 (m, 1H) 2.41-2.48 (m, 4H) 3.17-3.27 (m, 4H) 3.34-3.44 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.13 (m, 2H) 6.91 (d, J=9.09 Hz, 2H) 6.99 (d, J=2.02 Hz, 1H) 7.62 (d, J=2.02 Hz, 1H) 7.72 (d, J=9.09 Hz, 2H) 7.89 (d, J=7.83 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12](=[O:20])[CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.[NH2:25][C:26]([CH2:37][N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:39])([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]#[N:28].CN1CCOCC1>C(Cl)Cl>[CH2:40]([N:38]([CH2:37][C:26]([NH:25][C:9](=[O:11])[CH:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12](=[O:20])[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([C:27]#[N:28])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:39])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)C(CC1CCCCC1)C(=O)CN1CCOCC1
Reactant: CN(Cc1ccccc1)CC(N)(C#N)CCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CN(Cc1ccccc1)CC(C#N)(CCc1ccccc1)NC(=O)C(CC1CCCCC1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.7 %

Procedure:
2-Cyclohexylmethyl-4-morpholin-4-yl-oxo-butanoic acid (0.097 g, 0.34 mmol, 1.0 equiv) was dissolved in 10 mL of CH2Cl2 followed by addition of EDC (0.065 g, 0.34 mmol, 1.0 equiv). The solution was stirred for 15 min at which time a solution of 2-amino-2-[(benzyl-methyl-amino)-methyl]-4-phenyl-butyronitrile (0.10 g, 0.34 mmol, 1.0 equiv) in 5 mL of CH2Cl2 was added followed by N-methylmorpholine (0.137 g, 1.36 mmol, 4.0 equiv). The resulting solution was stirred at room temperature for 72 h. The volatiles were removed in vacuo and the residue was redissolved in 100 mL of EtOAc and the solution was washed 2×25 mL brine. The organic layer was evaporated to dryness and the crude product was purified by semi-prep reverse-phase HPLC using 40% CH3CN in water to 90% over a time of 25 min. The appropriate fractions were combined and concentrated to yield the desired product as a thick oil (0.047 g, 25%); MS, m/Z 559=M+1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.[CH:23]1([Mg]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CCOCC>[CH:23]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1cc2ccc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (131.8 mg, 0.4527 mmol) in tetrahydrofuran (6.0 mL, 74 mmol) in an oven-dried flask at 0° C. was added DPPPNiCl2 (18.2 mg, 0.0336 mmol) followed by 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL). The reaction was stirred at 0° C. for 1.5 hours and then heated at 40° C. overnight. DPPPNiCl2 (21 mg) and 2.0 M of cyclohexylmagnesium chloride in ether (0.60 mL) were added. The reaction was heated at 50° C. for an additional 3.5 hours. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 24.8 mg (19%) of N-(7-cyclohexylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.228, M+H=295.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.61 (dd, J=8.6, 1.7 Hz, 1H), 2.67 (t, J=11.7 Hz, 1H), 2.10-1.99 (m, 1H), 1.93-1.79 (m, 4H), 1.74 (d, J=12.3 Hz, 1H), 1.58-1.20 (m, 5H), 0.82 (dq, J=4.9, 2.9 Hz, 4H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH2:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][OH:42].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][OH:42])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC[C@H](N)CO
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CC[C@@H](CO)Nc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (S)-2-aminobutan-1-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (S)-2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-butan-1-ol. MS: (ES+) 461.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH:29]([OH:33])[CH2:30][CH2:31][OH:32].CCN(C(C)C)C(C)C.O(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:27][CH2:28][CH:29]([OH:33])[CH2:30][CH2:31][OH:32])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: NCC(O)CCO
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCC(O)CCO)c(-c2ccn[nH]2)c1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 500 mg, 1.253 mmol), 4-aminobutane-1,3-diol (Stage 97.1, 152 mg, 1.447 mmol), DIPEA (0.667 mL, 3.82 mmol) and iPrOH (2 mL) were added to a MW vial, which was sealed, flushed with argon and stirred at 130° C. for 20 h. The RM was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was treated with iPr2O and the resulting solid was filtered off and purified by flash chromatography (Silica gel column, 40 g, DCM/DCM-MeOH (9:1)) to afford the title compound as a white solid. UPLC-MS (Condition 8) tR=0.94 min, m/z=468 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.74 (m, 2H) 3.44-3.58 (m, 3H) 3.64-3.72 (m, 1H) 3.77-3.90 (m, 1H) 4.40 (t, J=5.07 Hz, 1H) 4.82 (d, J=5.38 Hz, 1H) 6.96 (t, J=1.96 Hz, 1H) 7.36 (d, J=8.93 Hz, 2H) 7.83-7.99 (m, 3H) 8.41 (d, J=2.32 Hz, 1H) 8.65 (d, J=2.20 Hz, 1H) 9.04 (s, 1H) 10.21 (s, 1H) 13.21 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C2C=C(C(O)=O)C(=CC=2)C(O)=O)=[CH:3][CH:2]=1.C(O[C:22](=[O:35])[C:23]1[CH:33]=[CH:32][C:31](Br)=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=1)C.N1C=CC(B(O)O)=CC=1.[Li]N1C(C)(C)CCCC1(C)C>C1COCC1>[O:35]=[C:22]1[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][C:4]=2[C:33]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][C:23]1=2
Reactant: CCOC(=O)c1ccc(Br)c(C(=O)OCC)c1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1C(=O)O
Agent: OB(O)c1ccncc1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1cnccc1-2

Procedure:
9-Oxo-9H-indeno[2,1-c]pyridine-7-carboxylic acid was obtained by allowing 4-pyridin-4-ylphthalic acid [FAB: 244 (M+H)+] which had been synthesized by carrying out the same operations of Reference Examples 27 and 28 using 4-bromoisophthalic acid diethyl ester and 4-pyridine boronic acid to undergo the reaction with lithium 2,2,6,6-tetramethylpiperidide at 0° C. in THF. By carrying out reaction of this compound by the same method of Reference Example 30, ethyl 9-oxo-9H-indeno[2,1-c]pyridine-7-carboxylate was obtained. FAB: 254 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:28])[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc2c(N)nc3c(c2n1CCCCNC(=O)N1CCOCC1)CCCC3
Yield: 79.7 %

Procedure:
Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-6, 7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with 4-morpholinecarbonyl chloride (0.43 mL, 3.7 mmol) to provide 1.14 g of N-[4-(4-amino-2-methyl-6, 7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide as an off white solid, m.p. 133.6-134.6° C. Analysis: Calculated for C20H30N6O2.1.1H2O: %C, 59.12; %H, 7.99; %N, 20.68; Found: %C, 58.77; %H, 7.53; %N, 20.46.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:41])[F:40])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[C:10]([CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:7]=1.[C:43](Br)(=[O:46])[CH2:44][CH3:45]>CN(C1C=CN=CC=1)C>[CH2:35]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:43](=[O:46])[CH2:44][CH3:45])[CH:3]=[CH:4][C:5]=2[C:39]([F:41])([F:40])[F:42])[N:9]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 67 %

Procedure:
Reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) with propionyl bromide (2 equivalents) in the presence of DMAP (1 equiv) according to the procedure of Example 69 gave a 67% yield of the title compound; homogeneous by TLC in 95:5 CH2Cl2 --MeOH.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].Br.[S:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.[CH2:18]=O.Br>CC(C)=O.C(O)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][S:12][CH2:13]2)=[CH:5][CH:6]=1
Reactant: C=O
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C1CNCSC1
Agent: Br
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(CCN1CCCSC1)c1ccc(F)cc1
Temperature: -5 °C
Yield: 83.7 %

Procedure:
A mixture containing 8.28 g (0.06 mol) of 4-fluoroacetophenone, 11.05 g (0.06 mol) of tetrahydro-1,3-thiazine hydrobromide, 2.70 g (0.09 mol) of paraformaldehyde, 25 ml ethanol and 0.1 ml of 48% hydrobromic acid is heated under reflux while stirring. After one hour an additional amount of 1.8 g (0.06 mol) of paraformaldehyde is portionwise added, the reaction mixture is heated for an additional 2 hours and then 80 ml of acetone are added. The mixture is cooled at -5° C. to give 12.73 g of product which is recrystallized from methanol to obtain 9.02 g (45.0%) of glistening crystalline hydrobromide of the title compound, m.p.: 210°-203° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1(N)CCCCC1>CN(C=O)C>[CH:27]1([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:28][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: On1nnc2ccccc21
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CCCCC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and cyclohexylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-cyclohexyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [C:1]1(S)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Cl.O[O:25][S:26]([O-:28])=O.[K+]>CC(=O)C>[CH3:18][O:19][C:20](=[O:23])[CH2:21][S:26]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:28])=[O:25]
Reactant: Sc1cccc2ccccc12
Reactant: COC(=O)CCl
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CS(=O)(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a stirred suspension of 3.1 g (0.019 mol) of naphthalene-1-thiol and 2.94 g (0.021 mol, 1.1 eq) of K2CO3 in 100 mL of propan-2-one cooled at 0° C., 3.15 g (0.029 mol, 1.5 eq) of chloro-acetic acid methyl ester were added in one portion. The ice bath was removed and the reaction mixture was stirred an additional 4 hours. The reaction was filtered, the solvent evaporated and the resulting residue was taken up in 100 mL of MeOH. 14.3 g (0.023 mol, 1.2 eq) of oxone (potassium peroxymonosulfate) were added and the reaction mixture was stirred over night at RT. The salts were filtered off, the solvent evaporated and the residue purified by column chromatography on silica gel with heptane/EtOAc (from 4:1 to 1:2) to afford 2.78 g (55%) of (naphthalene-1-sulfonyl)-acetic acid methyl ester as a light yellow oil, MS: 265 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:36][N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:44]=[CH:43][C:37]([C:38](=[O:39])[N:40]([CH3:41])[CH3:42])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(=O)N(C)C)cn3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The title compound was prepared in accordance with step (c) Example 38 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (120 mg, 0.28 mmol, see step (b) Example 1) and 6-chloro-N,N-dimethyl-nicotinamide (78 mg, 0.42 mmol). Yield 79 mg (48%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:19](=[O:49])[CH2:20][N:21]2[C:26](=[O:27])[C:25]3[CH:28]=[C:29]([CH2:31][CH3:32])[S:30][C:24]=3[N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[C:22]2=[O:48])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[CH:13]1([C:19](=[O:49])[CH2:20][N:21]2[C:26](=[O:27])[C:25]3[CH:28]=[C:29]([CH2:31][CH3:32])[S:30][C:24]=3[N:23]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:38][CH:39]=3)[C:22]2=[O:48])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(=O)C3CCCCC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C3CCCCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-{[3-(2-cyclohexyl-2-oxoethyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.57 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1.F[B-](F)(F)F.[C:20]([Si](C)(C)C)#[CH:21].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)#[CH:21]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1(c2ccccc2Br)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccccc1C1(C(=O)OC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of methyl 1-(2-bromophenyl)cyclopropanecarboxylate (I4) (658 mg, 2.58 mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol) t-Bu3PH.BF4 (37 mg, 0.13 mmol), CuI (25 mg, 0.13 mmol) and ethynyltrimethylsilane (0.44 mL, 3.1 mmol) in dry DMF (5.0 mL) was degassed with nitrogen for 10 minutes before the addition of Et3N (2.0 mL). After stirring at 65° C. under nitrogen for 16 hours the resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound I5 as an orange oil (569 mg, 81%); 1H NMR (400 MHz, d6-DMSO) δ 7.67-7.12 (m, 4H), 3.57-3.47 (m, 3H), 1.64-1.49 (m, 2H), 1.26-1.16 (m, 2H), 0.22-0.13 (m, 9H). LCMS-A: rt 6.977 min; m/z 273 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([CH:7]2[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[CH2:9][C:8]2=[O:16])=O)[CH2:3][CH2:2]1.Cl.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)#[N:19].CC(O)=O>CCO>[CH:1]1([CH2:4][C:5]2[C:7]3[C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][C:12]=3[N:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:27]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc(C#N)cc3)c2C1
Yield: 51.2 %

Procedure:
2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (111.1 mg, 0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (84.8 mg, 0.5 mmol, 1.0 eq) were suspended in 4 mL of 3:1 EtOH:AcOH and microwaved at 100° C. for 10 minutes. The solvent was removed in vacuo and the resultant residue purified by column chromatography to yield 81.8 mg (51% yield) of 4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile as an off-white powder.