Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]([O:16]C)=[O:15].Cl>>[C:14]([CH2:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:18])=[O:4])([OH:16])=[O:15]
Reactant: COC(=O)COc1ccccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccccc1C(=O)O
Temperature: 80 °C
Yield: 78.2 %

Procedure:
To 10% Solution of Sodium hydroxide (475 mL) was added 2-Methoxycarbonylmethoxy-benzoic acid methyl ester 5 (95 grams, 424 mmol) and heated to 80° C. for 4 hours. Reaction mixture was cooled to room temperature and pH adjusted so 2 with dilute Hydrochloric acid. The crude 80 was purified by dissolving in 10% NaOH and precipitating by acidifying with HCl, to get pure 80 (65 grams, 78.2%) as white powder. M.p: 189-192° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.Cl[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:21])[C:13](=[O:22])[CH2:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:10]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][CH2:12][C:13]1=[O:22]
Reactant: CC1CCNCC1
Reactant: CN1C(=O)CN=C(Cl)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCN(C2=NCC(=O)N(C)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
4-Methyl piperidine (1.56 g) was added to a solution of crude 5-chloro-1,2-dihydro-1-methyl-3H-1,4-benzodiazepin-2-one hydrochloride (0.005 mol) in dichloromethane (50 ml) cooled in ice. After warming to room temperature, sodium bicarbonate solution (20 ml) was added. The organic phase was separated, dried (Na2SO4) and evaporated to give an orange oil which was purified by column chromatography on silica with CH2Cl2 ∆CH2Cl2 :MeOH 95:5 as eluant to afford product.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:20][C:19]1[O:18][N:17]=[C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[C:13]1[N:14]=[C:10]([CH2:9][OH:8])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[CH:12]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CO)n1
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of 4-[2-benzyloxymethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (200 mg, 0.43 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic acid (0.98 mL) and trifluoromethanesulfonic acid (0.06 mL) and the resulting mixture stirred vigorously for 3 h. The mixture was then poured onto a saturated solution of sodium hydrogen carbonate and stirred for 30 min. The resulting precipitate was then filtered off, washed with water and then dried to afford the title compound (91 mg, 56%) which was obtained as a white solid. MS: m/e=377.4 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:39][CH:38]=1.CO>N1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41]([NH:34][C:30]2[N:29]=[CH:28][N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:12]2[O:13][C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11]2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:39][CH:38]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](OC(=O)c3ccccc3)[C@H](COC(=O)c3ccccc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of compound 4 (0.88 g, 1.92 mmol) in dry pyridine (40 mL) was added 4-monomethoxytrityl chloride (1.18 g, 3.84 mmol). The mixture was stirred at 60° C. for 24 h. After addition of methanol (5 mL), the solution was concentrated to dryness, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (30 mL), aqueous saturated NaHCO3 (30 mL) and water (30 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene to give pure 5 (1.01 g, 72%) as a foam: 1H NMR (CDCl3): δ 2.9-3.0 (m, 2H, H-2′ and H-2″), 3.62 (s, 3H, OCH3), 4.6-4.8 (m, 3H, H-4′, H-5′ and H-5″), 5.85 (pt, 1H, H-3′), 6.44 (dd, 1H, H-1′, J1′,2′=3.1 Hz, J1′,2″=7.3 Hz), 6.9 (br s, 1H, NH-6), 6.7-6.8 and 7.2-7.4 (2m, 24H, 2 benzoyls and MMTr), 7.97 and 8.13 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 732 [M+H]+, (FAB−) m/z 730 [M−H]−; UV (95% ethanol): λmax 274 nm (ε 12100), 225 nm (ε 24200), λmin 250 nm (ε 5900); [α]D20=−16 (c 1.12, DMSO).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:34])[OH:33])[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]1([CH3:56])[C:44]([CH3:46])([CH3:45])[O:43][B:42]([C:47]2[CH:48]=[N:49][N:50]([CH2:52][CH2:53][CH2:54]O)[CH:51]=2)[O:41]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:33])[O:34][CH2:54][CH2:53][CH2:52][N:50]4[CH:51]=[C:47]([B:42]5[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:39])([CH3:56])[O:41]5)[CH:48]=[N:49]4)[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propan-2-ylphosphinic acid (Compound 68B, 0.240 g, 0.389 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 97.9 g, 0.388 mmol) in 1,2-dichloroethane (8.53 mL) and DIPEA (0.812 mL, 4.66 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (1.21 g, 2.33 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent to afford the title compound as an off-white foam. MS (ESI): m/z 851.84/853.82 [M+H]+. UPLC: tR=1.57 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1F)[N:10]=[CH:9][N:8]=[C:7]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)([O-:3])=[O:2].[N:24]1([CH2:30][CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+].Cl>CS(C)=O.O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][C:13]([O:33][CH2:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: OCCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
6-nitro-4-(3-chloro-4-fluorophenylamino)-7-fluoro-quinazoline (1 eq.) and morpholine-propanol (1.5 eq.) were dissolved in DMSO (10 ml), the solution was stirred for 5 mins with a water bath. A solution of potassium tert-butoxide (3.0 eq.) in DMSO (5 ml) was added slowly to the solution mentioned-above in drops, the mixture was stirred at room temperature for further 30 mins. After the reaction finished, the mixture was diluted with 100 ml water and pH was adjusted to neutral with concentrated hydrochloric acid, then stirred for 30 mins, large amount of yellow solid was precipitated, then filtering, the filter cake was washed with water twice and dried to give yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (yield 90%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]2=[C:9]([CH3:17])[N:10]=[C:11]([CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:4]2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>COCCOCCOC>[NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:9]([CH3:17])[N:10]=[C:11]([CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:4]2[N:3]=1
Reactant: CCC(C)Cc1nc(C)c2c(=O)[nH]c(N)nn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOCCOC
Product: CCC(C)Cc1nc(C)c2n1N=C(N)NC2

Procedure:
2-Amino-5-methyl-7(2-methylbutyl)imidazo[5,1-f]-as-triazin-4(3H)-one (1.7 g.) and lithium aluminium hydride (0.9 g.) in diglyme (50 ml., freshly redistilled) were stirred and heated to 100° for 4.5 hours and cooled. Water (1 ml.) was added dropwise, followed by 2N sodium hydroxide (2 ml.) and water (1 ml.). The solid was filtered off, the filtrate was evaporated and the residue was crystallised from isopropanol. The product had m.p. 207°-213° (63%). It was converted to its hydrochloride, m.p. 203°-205.5° by treating a solution in ethanol with hydrogen chloride in ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH2:48][CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH2:48][CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (421 mg, 88%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 427 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH2:14][CH3:15])[C:6](=[O:16])[C:5]2([CH3:18])[CH3:17]>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:14][CH3:15])[C:6](=[O:16])[C:5]2([CH3:17])[CH3:18]
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Yield: 37.9 %

Procedure:
Analogously to general procedure (II) the compound (1,3 g) is prepared from A2 (3.9 g) in MeOH (160 ml) using Pd/C (0.4 g) as a catalyst (12 h).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]#[N:6]
Reactant: CC(C)(C(N)=O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC(C)(C#N)C(F)(F)F
Temperature: 200 °C

Procedure:
A mixture of 3,3,3-trifluoro-2,2-dimethyl-propionamide (Stage 44.4) (121.2 mmol) and phosphorus pentoxide (121.2 mmol) was slowly heated to 200° C. and the resulting distillate collected. The title compound was obtained as a colorless liquid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][N:44]=1>CN(C=O)C>[NH2:42][C:43]1[N:44]=[CH:45][C:46]([C:47]([N:3]2[C@@H:4]([CH3:8])[CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:48])=[CH:50][CH:51]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[C@H]1COC[C@H](C)N1
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: C[C@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].CCOC(C)=O.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C#N)c(O)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of the iodide product from Step B (101 g, 0.36 mol) and zinc(II)cyanide (30 g, 0.25 mol) in 400 mL of dry DMF was degassed by bubbling argon through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium (8.5 g, 7.2 mmol) was added, and the solution was heated to 80° C. for 4 hours. The solution was cooled to room temperature, then stirred for an additional 36 hours. The reaction was poured into EtOAc water, and the organic layer was washed with brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the crude product. Purification by column chromatography through silica gel (30%-50% EtOAc/hexane) provided the titled product.
Reaction SMILES: [N:1]([O-:3])=[O:2].[K+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]=1.N>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: C1=NCCc2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
15 g of potassium nitrite was added to a concentrated sulfuric acid (70 ml) solution containing 18 g (0.14 mol) of 3,4-dihydroisoquinoline was added thereto at −15° C. over 20 minutes. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 40 minutes. The reaction solution was poured into ice-water and basified with an aqueous ammonia. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. After concentrating, decaline (100 ml), nitrobenzene (100 ml) and 2 g of Pd-Black were added to the residue, and the mixture was heated at 200° C. overnight in nitrogen stream. The reaction solution was washed with ethyl acetate and then extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and then an aqueous sodium hydroxide was added thereto. The resulting precipitates were collected by filtration and washed with water, to give 14.4 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=1)[NH2:23]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([CH2:27][S:28][CH3:29])[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: COc1cc(N)cc(CSC)c1
Product: COc1cc(CSC)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1

Procedure:
Intermediate 32.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-methoxy-5-[(methyl-sulfanyl)methyl]aniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 7:3) to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:8]([OH:17])[C:9]([F:16])([F:15])[C:10](OCC)=[O:11])[CH:7]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([CH:8]([OH:17])[C:9]([F:16])([F:15])[CH2:10][OH:11])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)C(O)c1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCC(F)(F)C(O)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-(5-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (20.0 g, 61.3 mmol) in MeOH (160 mL), NaBH4 (7.0 g, 184.2 mmol) was added portion wise over a period of 30 min. at 0° C. Stirring was continued for 1 h at 0° C. and reaction was monitored by TLC. Upon complete consumption of the starting material, reaction mass was concentrated under reduced pressure and treated with saturated ammonium chloride solution. The crude reaction mass was dissolved in ethyl acetate and organic layer was washed with brine (15 mL) followed by drying over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to furnish title compound with sufficient purity. Yield=17 g (97%). TLC (50% ethyl acetate in Hexane): Rf=0.32),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:31][O:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1>CN(C1C=CN=CC=1)C>[CH3:31][O:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:36]([C:41]([F:43])([F:42])[F:44])[CH:35]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-trifluoromethyl-benzoic acid methyl ester (CAS Reg. No. 34040-64-7 167760-75-0) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=574.4 [M+H+].
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 423.12 g/mol.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1.[I:13]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[S:3][C:4]([I:13])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCCCCc1csc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCCCCCc1nc(Cl)sc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
5.30 g (26.0 mmol) of 2-chloro-4-hexylthiazole and 7.02 g (31.2 mmol) of N-iodosuccinimide were dissolved in 40 mL of acetonitrile, and stirred for 2 hours at 50° C. under argon gas purge. The resultant reaction mixed liquid was washed with a Na2S203 aqueous solution, and the aqueous layer was extracted with chloroform and added to the organic layer. The organic layer was concentrated, and subjected to silica gel column chromatography (development solvent:chloroform/hexane=1/1 (volumetric ratio)) to take out red transparent liquid. Since a peak of a molecular weight of 330 containing one chlorine atom was observed in the mass spectrum (apparatus: HP-6890GC/HP-5973MSD, column: SGE BPX-5 (30 m×0.25 mm I.D.×025 μm), column temperature: 50° C. (5 minutes)→10° C./min.→350° C. (held for 5 minutes), injection port temperature: 280° C., carrier gas: He, 1.0 ml/min.), it could be confirmed that the above-described red transparent liquid was the intended 2-chloro-4-hexyl-5-iodothiazole. The amount obtained was 7.50 g, and the yield was 87.6%.