Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:22][C:23]([NH2:25])=[NH:24])=[N:5][CH:4]=1.Cl.N[C:28](N)=N.O>CS(C)=O>[CH3:28][O:20][C:19](=[O:21])[C@@H:17]([CH3:18])[NH:16][S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:11][CH:10]=1)(=[O:14])=[O:15]
Reactant: C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Reactant: N=C(N)N
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 4.9 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine hydrochloride ##STR33## NaH (35 mg, 80% dispersion by wt in mineral oil, 1.17 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (179 mg, 1.87 mmol) in DMSO (5 mL) and the mixture was heated at 60° C. under N2 for 45 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-alanine methyl ester (170 mg, 0.47 mmol) was added and the mixture heated at 90° C. for 4 h. The cooled mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (66:33 to 0:100) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine methyl ester (22 mg, 0.057 mmol) as a yellow foam/oil.
Reaction SMILES: [F:1][C:2]1([F:20])[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([N:4]1[CH2:3][C:2]([F:1])([F:20])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 65.4 %

Procedure:
To a mixture of crude tert-butyl 10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (65.0 mg, 0.222 mmol) and K2CO3 (61.5 mg, 0.445 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-bromobut-2-yne (29.2 μL, 0.334 mmol) and the reaction heated at 45° C. for 48 h. The reaction was diluted with ethyl acetate and filtered. The filtrate was dried over Na2SO4, filtered and concentrated. Silica gel chromatography (4 g silica, 1-100% ethyl acetate/hexane) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 65%) as a colorless oil. ESI-MS m/z calc. 344.2. found 345.3 (M+1)+; Retention time: 1.91 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.80 (br s, 2H), 3.35 (q, J=2.2 Hz, 2H), 3.23 (t, J=12.1 Hz, 2H), 2.80 (t, J=8.5 Hz, 2H), 2.48 (s, 2H), 2.02 (d, J=13.2 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.54-1.48 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[C:33]2([C:52]4[C:43](=[CH:44][C:45]5[O:50][CH2:49][CH2:48][O:47][C:46]=5[CH:51]=4)[O:42][CH2:41]2)[C:34](=[O:40])[NH:35]3)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[C:33]2([C:52]4[C:43](=[CH:44][C:45]5[O:50][CH2:49][CH2:48][O:47][C:46]=5[CH:51]=4)[O:42][CH2:41]2)[C:34](=[O:40])[N:35]3[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3ccc(Oc4ccccc4)cc3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 196-199° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 8.61-8.57 (m, 1H), 7.69-7.65 (m, 1H), 7.40-7.18 (m, 5H), 7.12-7.05 (m, 1H), 7.02-6.97 (m, 2H), 6.93-6.86 (m, 2H), 6.84-6.71 (m, 4H), 6.39 (s, 1H), 6.21 (s, 1H), 5.26 (d, J=15.8 Hz, 1H), 4.95 (d, J=15.8 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.43 (d, J=9.0 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 157.4, 156.3, 155.6, 149.6, 144.7, 142.4, 139.8, 137.9, 137.1, 133.5, 130.4, 130.1, 129.7, 128.7, 125.4, 123.1, 122.8, 122.3, 121.7, 118.6, 118.4, 111.2, 108.7, 99.3, 77.9, 64.5, 64.0, 58.5, 46.2; MS (ES+) m/z 555.0 (M+1).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([Cl:19])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:27]>CS(C)=O>[ClH:19].[ClH:19].[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[NH2:27])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: CS(C)=O
Product: Cl
Product: N[C@H]1CCCC[C@H]1Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.5 ml (5 equivalents) of cis-1,2-diaminocyclohexane, and the mixture is then heated at 120° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 3 ml of ethanol and 3 ml of HCl-EtOH (hydrochloric acid-ethanol) are added. 34.3 mg of expected product are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][NH:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CNC4CCNC4)ncn3)ccc21

Procedure:
(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 3.30 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is then extracted with EtOAc (3×) and the combined organic layers are washed with water, brine, dried with Na2SO4, filtered, and condensed. The residue is purified by FCC (0-10% 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 496.8 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1H), 8.36 (d, J=8.84 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=3.54 Hz, 1H), 7.88 (s, 1H), 7.57 (t, J=7.83 Hz, 1H), 7.44 (d, J=7.83 Hz, 1H), 7.42 (d, J=2.27 Hz, 1H), 7.03-7.13 (m, 2H), 6.75 (d, J=3.79 Hz, 1H), 3.80-3.85 (m, 2H), 2.81-3.02 (m, 3H), 2.52-2.75 (m, 2H), 2.19-2.35 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:9]([C:17]#[N:18])=[C:8]([C:19]#[N:20])[N:7]=1.Cl[C:22]1[C:27](Cl)=[N:26][C:25]([C:29]#[N:30])=[C:24]([C:31]#[N:32])[N:23]=1.COCCOCCOC>C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:6]2[N:7]=[C:8]([C:19]#[N:20])[C:9]([C:17]#[N:18])=[N:10][C:11]=2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:22]2[N:23]=[C:24]([C:31]#[N:32])[C:25]([C:29]#[N:30])=[N:26][C:27]1=2
Reactant: COCCNc1nc(C#N)c(C#N)nc1NCCOC
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: COCCN1c2nc(C#N)c(C#N)nc2N(CCOC)c2nc(C#N)c(C#N)nc21

Procedure:
FIG. 17 shows the reaction pathway. In a 100 mL round-bottom flask having a magnetic stir-bar and with 14/20 glass joint attached to an air-condenser was add 0.48 g [0.002 mole] of 2,3-bis(2-methoxyethylamino)-5,6-dicyanopyrazine 1101, 2,3-dichloro-5,6-dicyanopyrazine 301 and 5 mL of diglyme 901 [diethyleneglycoldimethylether]. The reaction was stirred for about an hour until all the solids had dissolved. To this solution was added 0.6 g of diisopropylethylamine 902 drop-wise with stirring. The reaction was then brought to reflux using a sand-bath at ˜180°. All under a nitrogen sweep. The solution acquired a dark gray orange color as heating took place. Reaction was monitored by TLC or column chromatography [silica plates] using ethyl acetate; the bright blue fluorescent starting material spot at Rf: 0.45 slowly faded and was converted to a bright yellow spot at Rf: 0.98 identical to the material formed from dimerization. After 5 hours the starting material spot remained though the yellow spot corresponding to the expected product at solvent front in TLC or column chromatography was present. Solution cooled to rt and poured, with good stirring into 40 mL of water/ice mixture having ˜0.5 mL of 10% HCl. Dark mixture was allowed to stand ˜24 hrs and filtered by suction and washed with water. Material was dried in vac. drying oven at 70°. There was obtained 0.6 g of yellow brown powder having both starting material and desired tetracyanodipyrazinepyrazine. Exact mass 402.2 [calc 402.13].
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][C:10](=O)[N:9]=[C:8]2[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+].CN(C)[CH:28]=[O:29]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([CH:28]=[O:29])=[C:10]([Cl:21])[N:9]=[C:8]2[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCC1=NC(=O)CN1Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(Br)cc1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
1.61 g of 1-(4-bromo-benzyl)-2-butyl-1,5-dihydroimidazol-4-one and 10 ml of toluene are loaded into a round-bottom flask. The mixture is cooled down to 0–5° C., then added dropwise with 1.4 ml of phosphorous oxychloride. The temperature is slowly allowed to reach 90° C. and 1.2 ml of dimethylformamide are added dropwise. The mixture is heated at 115° C. for 2 h, then cooled to room temperature and added with 50 ml of toluene, 100 g of crushed ice and 10 g of celite. Stirring is continued for 30 minutes, then the pH is adjusted to 8 with 30% aqueous NaOH and the precipitate is filtered off using a Buchner funnel. The organic phase is concentrated under vacuum and chromatographed eluting with 1:1 v/v hexane-diethyl ether. 380 mg of product (IV) as a colourless oil is obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].C(OC1C(OC)=CC(C(O)=O)=C([N+]([O-])=O)C=1)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46]CNC[CH2:42]1>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:42][CH2:3][N:2]([CH:4]=[O:5])[CH2:1][CH2:46]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(C)C=O
Agent: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C=O)CC1
Reaction time: 6 h
Yield: 93 %

Procedure:
DMF was added to a stirred suspension of 4-benzoyloxy-5-methoxy-2-nitro benzoic acid (6) (0.500 mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6 h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added drop wise over a period of 1 h to a stirred suspension of 1-(2-methoxyphenyl)piperazine (316 mg 15.6 mmol) triethyl amine (5 ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCl and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of 2-amino-4-benzyloxy)-5-methoxyphenyl][4-(2-methoxyphenyl)piperazino]methanone (7a) in 93% yield (670 mg, 85% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.40-3.55 (m, 4H), 3.85 (S, 3H), 3.95 (s, 3H), 5.20 (s, 2H), 6.80-7.00 (m, 5H), 7.30-7.50 (m, 5H), 7.70 (s, 1H); FABMS: 477 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl>Cl>[ClH:16].[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Product: NNc1ccc2ncccc2c1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of quinolin-6-ylamine (5 g, 35 mmol) in conc. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO2 (2.42 g, 35 mmol) at 0° C. The resulting mixture was stirred for 1 h and then treated dropwise with a solution of SnCl2 2H2O (15.8 g, 70 mmol) in conc. HCl (15 mL) at 0° C. The reaction mixture was stirred for 2 h at RT. The precipitate was collected and washed with EtOH and Et2O to yield 1-(quinolin-6-yl)hydrazine hydrochloride as a yellow powder (4.3 g, 77% yield), which was used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C(C(Cl)C[O:31]CC(Cl)[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(C1C=CC=CC=1)C1C=CC=CC=1.N[C@H:50]([C:62]([OH:64])=[O:63])CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C:41]1([CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:63][CH2:62][CH2:50][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[C:62](=[O:63])([O-:31])[O-:64]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClC(COCC(Cl)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([O-])[O-]
Product: c1ccc(C(OCCOc2ccc(N3CCNCC3)cc2)c2ccccc2)cc1
Temperature: 70 °C
Yield: 202.7 %

Procedure:
4-(4-Hydroxyphenyl)piperazine (0.356 g, 2 mmol) is added to a stirred suspension of NaH (0.088 g of 60% oil dispersion (2.2 mmol)), washed and decanted with pentane) in DMF (5 mL) under N2 and the reaction mixture was heated to 70° C. for approximately 10 min (until the effervescence ceased). Benzhydrylchloroethylether (0.542 g, 2.2 mmol) in DMF (1.5 mL) was added, followed by Nal (0.331 g, 2.2 mmol). The reaction mixture was stirred and heated to 90°-100° C. for 48 h. DMF was removed in vacuo and the residue triturated in CHCl3. The insoluble solids removed by filtration, washed (CHCl3) and the combined organic extracts were washed with water, dried (Na2 SO4) and evaporated in vacuo to afford an oily residue (1 g). The residue is purified by column chromatography on silica gel using an increasing proportion of MeOH in CH2Cl2 containing 0.5% Et3N to give a colorless foamy solid (0.416 g, 53%). Traces of residual Et3N are removed by washing with CH2Cl2, dried (Na2SO4) and evaporation in vacuo to afford shiny crystalline flakes: mp 106°-108° C.: 1H NMR (DMSO-d6) d 9.14 (s, 1H), 7.4-7.2 (m, 10H), 6.91 (q, 4H), 5.57 (s, 1H), 4.12 (t, 2H), 3.71 (t, 2H), 3.21 (br s, 8H): IR 3361, 2925, 2834, 1674, 1516, 1496, 1452, 1252 cm-1. MS 389 (MH+). Anal. CaIc'd. for C25H28 N2O2 ·2 H2O: C, 64.18, H, 7.04, N, 5.76. Found: C, 64.49, H, 6.85, N, 6.06.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7]O)=[N:3]1.O=S(Cl)[Cl:11]>>[ClH:11].[Cl:11][CH2:7][C:4]1[N:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cnc(CO)n1
Product: Cl
Product: Cn1cnc(CCl)n1

Procedure:
(1-methyl-1H-1,2,4-triazol-3-yl)methanol (0.25 g, 2.2 mmol) was dissolved in 10 mL of SOCl2 and refluxed for 2 hours. The mixture was evaporated to dryness and coevaporated with toluene. The resulting white solid (0.2 g) was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:34][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: COC(=O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (1-1) (1.1 g) in tetrahydrofuran (7 ml) and water (2 ml) is added, at room temperature, lithium hydroxide monohydrate (0.28 g). The mixture is stirred at room temperature for 20 minutes, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.82 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:25]([F:27])([F:28])[F:26])[CH2:24][CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
90 mg (purity 69%, 0.14 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoic acid (racemate) and 29 mg (0.15 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 58 mg (67% of theory)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][N:21]3[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[N:14][CH:13]=1.C([N-]CC)C>CS(C)=O>[Cl:26][C:24]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[S:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])=[C:17]([C:15]2[O:16][C:12]([CH2:11][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:13][N:14]=2)[CH:25]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Agent: CC[N-]CC
Solvent: CS(C)=O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
DMSO (7 vols, 70 ml) and isopropylpiperazine (1.5 eq, 0.387 wt, 0.431 vol, 4.31 ml, 3.87 g) are charged to a clean vessel. 5-(Bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (1.0 eq, 10 g (9.13 g corrected for assay), 1 wt) is added in 5 portions at 20° C. over 1 hr and the mixture stirred for 1 hr. The mixture is heated to 50° C. and aged for 1 hr, then checked for consumption of starting material by HPLC. Diethylamide (1.2 eq, 0.244 wt, 0.336 vol, 2.44 g, 3.36 ml) is added over 10 mins and the mixture aged for 30 mins, then cooled to 20° C. over 1 hr and further aged for 2 hrs. The thick slurry is filtered and washed with DMSO (2×1.5 vols, 2×15 ml) followed by acetone:water 1:2 (3×2 vols, 3×20 ml). The resultant solid is blown dry on the filter and dried at 60° C. in vacuo to constant weight/temperature to afford 2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole as an off-white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:16]([O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: C=CC(=O)OCC
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
A 104 mg portion of palladium acetate and 5 ml of TEA were added one by one to 50 ml of acetonitrile solution containing 7.44 g of 3-iodobenzoic acid and 3.9 ml of ethyl acrylate, and the mixture was sealed in a tube and heated at 100° C. for about 12 hours. After spontaneous cooling, the catalyst was removed by filtration while washing with appropriate amounts of methanol and ethyl acetate, and the filtrate was evaporated under a reduced pressure. The thus formed crude crystals were recrystallized from a small amount of ethanol to obtain 5.82 g (88%) of 3-(3-ethoxy-3-oxoprop-1-en-1-yl)benzoic acid as white crystals. FA: 221
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CC#N.O.CC#N>O>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: C1CCNCC1
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN2CCCCC2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 5 from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and piperidine. MS (LC-MS): 462.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.74 min.