Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([C:34](=[O:36])[CH3:35])[CH3:37])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Yield: 55.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(N-methylacetamido)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72 mg, 112 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-{1-[3-(acetyl-methyl-amino)-propyl]-5-difluoromethoxy-1H-indazol-3-yl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (32 mg, 56%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.39 (s, 1H), 8.22 (br. s., 1H), 7.84-7.98 (m, 2H), 7.40 (d, J=9.8 Hz, 1H), 6.93-7.47 (m, 1H), 4.48-4.60 (m, 1H), 3.36-3.42 (m, 2H), 2.95 (s, 3H), 2.79 (s, 3H), 1.93 (d, J=7.5 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1cccc(N)c1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@@H](Nc1nc(Nc2cccc(S(C)(=N)=O)c2)ncc1Br)C(C)(C)O

Procedure:
127 mg (0.43 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1 ml of acetonitrile is added to 74 mg (0.43 mmol) of (RS)—S-(3-aminophenyl)-S-methyl sulfoximide in 0.5 ml of acetonitrile. It is mixed with 0.1 ml of a 4N solution of HCl in dioxane, and the batch is refluxed overnight. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 37 mg (0.09 mmol, corresponding to 20% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:63][CH:64]([C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH3:75])([CH3:74])[O:72][B:71]([OH:76])[C:70]=2[CH:77]=1)[CH3:65]>CN(C=O)C.CC(=O)OCC>[OH:76][B:71]1[C:70]2[CH:77]=[C:66]([CH:64]([NH:63][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:27]([F:30])([F:28])[F:29])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH3:65])[CH:67]=[CH:68][C:69]=2[C:73]([CH3:74])([CH3:75])[O:72]1
Reactant: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.33 mmol), HATU (188 mg, 0.495 mmol) and Et3N (0.15 mL, 0.99 mmol) in DMF (10 mL) can be added 6-(1-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (0.93 mmol). The mixture can be stirred at rt overnight and EA (50 mL) can be added. The mixture can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17](O)=[O:18])([O-:3])=[O:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:17](=[O:18])[CH2:16][C@@H:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a mixture of Example 10D (0.75 g) and morpholine (0.318 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylpyridin-4-amine (0.445 g) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.699 g). The mixture was stirred overnight, diluted with ethyl acetate and washed with 5% aqueous HCl and water. The organic layer was dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C@H:13]([OH:21])[C@@H:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[N:19]O)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O>CO.[Ni]>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C@H:13]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11][CH2:12]1)[OH:21]
Reactant: ON=C1CCC[C@H]1[C@@H](O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: N[C@@H]1CCC[C@H]1[C@@H](O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.71 %

Procedure:
A mixture of Example 220B (200 mg, 0.609 mmol) in MeOH (25 mL) was added to Ra—Ni 2800, (water slurry, 500 mg, 9.93 mmol) in a 50 mL pressure bottle and stirred for 16 hours at 30 psi at room temperature, and filtered through a nylon membrane. The filtrate was concentrated and purified using a Waters C8 OBD SunFire 30 mm×75 mm column eluted with acetonitrile/0.1% TFA to afford Example 220C in 4.71% yield. MS (ESI+) M/Z 314 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.4, 2.1 Hz, 1H), 5.85 (d, J=4.3 Hz, 1H), 3.74 (dd, J=9.7, 3.5 Hz, 1H), 3.21-3.29 (m, 1H), 2.06-2.38 (m, 5H), 1.10-1.88 (m, 10H);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27][C:28](O)=[O:29])=[CH:25][N:24]=[C:23]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:22]=2)[CH2:20][CH2:19]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:28](=[O:29])[CH2:27][C:26]2[C:21]([CH:18]3[CH2:19][CH2:20]3)=[N:22][C:23]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:24][CH:25]=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[4-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[N:3]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:24])[C:5]=2[F:25].[CH:34]1(B(O)O)[CH2:36][CH2:35]1.CC([O-])=O.[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:6]1[C:5]([F:25])=[C:4]2[C:9]([C:10]([S:11][C:12]3[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:34]3[CH2:36][CH2:35]3)[N:3]2[C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=2)=[CH:8][CH:7]=1
Reactant: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: CCCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
To a stirred solution of compound 3 (260 mg, 0.47 mmol) in DME (5 mL) under inert atmosphere were added cyclopropylboronic acid (40.4 mg, 0.47 mmol), Pd(dppf)2Cl2 (69 mg, 0.09 mmol), KOAc (138 mg, 1.41 mmol) at RT; heated to 90° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 7-9% EtOAc/Hexanes to afford 70 mg of compound 4 which was further purified by preparative HPLC to afford pure compound 4 (20 mg, 9%) as a yellow syrup. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.64-7.60 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 7.10-7.06 (m, 1H), 6.95-6.91 (m, 1H), 6.79-6.75 (m, 1H), 4.41 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.00-1.93 (m, 2H), 1.74-1.67 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.08-1.06 (m, 2H), 0.99 (t, J=7.2 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 99.9%; m/z 516.5 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.00 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][C:5]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[ClH:36]>ClCCl>[ClH:36].[Cl:36][CH2:10][C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[N:6]=1
Reactant: OCc1ccn2ccnc2n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccn2ccnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of imidazo[1,2-α]pyrimidin-7-ylmethanol (4.64 g, 34.1 mmol) in dichloromethane under an atmosphere of nitrogen was added triphenylphosphine (10.6 g, 40.5 mmol) and carbon tetrabromide (13.4 g, 40.5 mmol). This mixture was stirred at room temperature for 2.5 h before addition of ethereal hydrogen chloride (1.0M, 100 ml) in a dropwise manner and allowed to stir at room temperature for a further 1 h. Reaction mixture was evaporated to dryness under reduced pressure and the resulting solid washed with dichloromethane followed by ether and then dried under vacuum to give 7-chloromethylimidazo[1,2-α]pyrimidine hydrochloride salt (5.0 g, 79%) as a pale brown solid: δH (360 MHz, d6-DMSO) 5.06 (2H, s), 7.77 (1H, d, J 7), 8.31-8.35 (2H, m), 9.37 (1H, d, J 7); m/z (ES+) 168, 170 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[NH2:29][CH2:30][CH2:31][OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:29][CH2:30][CH2:31][OH:32])=[O:21]
Reactant: NCCO
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCO)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-aminoethanol. 1H NMR (400 MHz, CDCl3) δ ppm 3.10 (s, 3 H) 3.39 (s, 3 H) 3.53-3.57 (m, 2 H) 3.78-3.81 (m, 2 H) 6.81 (t, J=8.0 Hz, 1 H) 7.47-7.52 (m, 2 H) [M+H] calc'd for C15H16FIN4O4, 463; found, 463.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.[O:59]=[C:60]1[CH:64]=[CH:63][C:62](=[O:65])[N:61]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][NH2:74])=[O:72]>>[O:65]=[C:62]1[CH:63]=[CH:64][C:60](=[O:59])[N:61]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][NH:74][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:72]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 152, from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Cl

Procedure:
The benzoimidazol-2-one from step (b) above (1.43 g, 6.0 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 254.9 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH2:15][C:16]#N)[CH:14]=1)C1C=CC=CC=1.O.C(O)(=O)C>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][C:10]=1[C:21]([F:24])([F:23])[F:22])[NH:18][CH:16]=[CH:15]2
Reactant: N#CCc1cc(OCc2ccccc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Oc1cc2cc[nH]c2cc1C(F)(F)F
Yield: 84.4 %

Procedure:
5-Benzyloxy-2-nitro-4(trifluoromethyl)phenylacetonitrile (2.22 g, 6.6 mmol) was dissolved in ethanol (45 ml), water (5 ml) and acetic acid (0.32 ml) then hydrogenated with 10% palladium on carbon at 1 atmosphere pressure for 2 hours. The catalyst was filtered off and filtrate evaporated to give 5-hydroxy-6-trifluoromethylindole (1.12 g, 84%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.CN(C)C.[CH2:17]([O:19][C:20]([C:22]1([CH2:37][OH:38])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:23]1)=[O:21])[CH3:18].C(N(CC)CC)C>ClCCl.O>[CH2:17]([O:19][C:20]([C:22]1([CH2:37][O:38][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1(CO)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
4-Toluenesulphonyl chloride (131 g, 687 mmol) and trimethylamine hydrochloride (43.8 g, 458 mmol) were added to 3-hydroxymethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (140.7 g, 457.8 mmol) (see Preparation 10) and triethylamine (160 mL, 1140 mmol) in dichloromethane (1400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 hours then at RT for 18 hours. Cooled to 0° C. and trimethylamine hydrochloride (21.9 g, 229 mmol) was added, followed by 4-toluenesulphonyl chloride (17.45 g, 91.6 mmol). The reaction mixture was stirred at 0° C. for 4 hours. Water (500 mL) was added and stirred for 10 minutes. The reaction mixture was washed with 2M citric acid aqueous solution (1400 mL) and saturated aqueous NaHCO3 (1400 mL). The organic layer was separated, washed with water (1300 mL) then concentrated under reduced pressure to afford the title compound as a brown oil (215.15 g, 100%).
Reaction SMILES: C[O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[OH:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: CN1CCCC1=O
Product: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
N-[7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Step 6, 1.0 g, 2.15 mmol) in NMP (20 mL) was heated to 100° C. and Na2S (0.84 g, 10.76 mmol) was added portionwise. The reaction was heated to 160° C. for 10 min and cooled to rt and concentrated under reduced pressure. The resulting slurry was diluted with water (100 mL) and the pH adjusted to 7 by the slow addition of aqueous 1N HCl and the mixture was stirred 2 h. The solid was collected via vacuum filtration and washed with water (50 mL) and finally triturated with CH2Cl2/heptane (10 mL). High vacuum drying overnight gave the title compound (0.49 g, 51%): HPLC MS RT=0.21 min, MH+=451; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.14-2.26 (2H, m), 3.03-3.17 (2H, m), 3.32-3.54 (4H, m), 3.60-3.72 (2H, m), 3.95-4.05 (2H, m), 4.18-4.35 (4H, m), 4.51-4.64 (2H, m), 7.38 (1H, d), 7.68 (1H, dd), 7.82 (1H, d), 8.63 (1H), 8.84 (1H, dd), 9.42 (1H, s), 13.39 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].B.Cl>C1COCC1>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1cccs1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCCCCc1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a cool (0°) solution of 10.0 g of 4-thienylbutyric acid (58.8 mmol) in 60 ml of dry THF was added 59 ml of a 1M solution of borane in THF, dropwise with stirring over one hour. The mixture was stirred for an additional 5 hours. The reaction mixture was poured onto 200 g of ice. This mixture was acidified with 2N HCl and the product extracted into ethyl acetate. The extract was washed with brine, dried (Na2SO4) and evaporated to give 8.5 g of a colorless oil (93%). 1H-NMR (CDCl3)δ7.0 (1H, t); 6.75 (2H, m); 3.5 (2H, t); 2.75 (2H, t); 1.6 (4H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:8].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=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>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:21]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])[CH:3]=[CH:4][C:5]=1[F:22]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CNC(=O)c2cc(Br)ccc2F)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(F)c(C(=O)NCc2ccc(OC)c(OC)c2)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (200 mg) in dimethylformamide (2 mL) were added methyl acrylate (0.068 mL), triethylamine (0.09 mL) and dichlorobis(triphenylphosphine)pailadium(II) (13.4 mg), and the mixture was stirred for 6 hours at 120° C. in a sealed tube. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2-(methoxycarbonyl)ethenyl]benzamide (117 mg) as a solid substance.
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]3[N:30]=[CH:31][CH:32]=[CH:33][C:24]4=3)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](I)[CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[I:34][C:35]1[CH:36]=[C:37]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([C:14]4[C:13]5[C:8]([C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[C:20]6[C:15]=4[CH:16]=[CH:17][CH:18]=[CH:19]6)=[CH:9][CH:10]=[CH:11][CH:12]=5)=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:32][CH:31]=[N:30][C:25]2=3)[CH:38]=[CH:39][CH:40]=1
Reactant: c1ccc(-c2c3ccccc3c(-c3ccc4[nH]c5ncccc5c4c3)c3ccccc23)cc1
Reactant: Ic1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Ic1cccc(-n2c3ccc(-c4c5ccccc5c(-c5ccccc5)c5ccccc45)cc3c3cccnc32)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
6-(10-phenylanthracen-9-yl)-9H-pyrido[2,3-b]indole (1.76 g, 4.19 mmol), 1,3-diiodobenzene (2.76 g, 8.37 mmol), CuI (319 mg, 1.67 mmol), K3PO4 (1.78 g, 8.37 mmol), trans-1,2-dicyclohexanediamine (0.2 mL, 1.67 mmol) were put in a 250 mL two-neck flask and dissolved in 1,4-dioxane. The solution was refluxed and stirred at 120° C. for 12 hours. After completion of the reaction, the solution was extracted with methylenechloride and H2O and was distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of hexane and methylenechloride (1:5). The solution was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (1.66 g, yield: 63%).