Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1cnc(N2CCCNCC2)nc1
Temperature: 25 °C
Yield: 48 %

Procedure:
50 ml of acetonitrile was added to 10.0 g (0.1 mole) of homopiperazine, 2.9 g (0.025 mole) of 2-chloropyrimidine, 6.9 g (0.05 mole) of potassium carbonate and a catalytic amount of potassium iodide, and the mixture was refluxed under heating for 11 hours. The mixture was cooled to room temperature and then filtered, the filtrate obtained was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=8:2 mixed solution) to obtain 2.14 g of 1-(2-pyrimidyl)homopiperazine as a pale yellow liquid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31](O)=[O:32])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17].[O:34]=[C:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31]([N:39]3[CH2:38][CH2:37][NH:36][C:35](=[O:34])[CH2:40]3)=[O:32])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C1CNCCN1
Reactant: COc1cncc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.06 ml (0.32 mmol) of N,N-diisopropylethylamine is added to a solution of 150 mg (0.16 mmol, 37% purity) of the compound of Example 64A, 32 mg (0.32 mmol) of 2-oxopiperazine, and 97 mg (0.26 mmol) of HATU in 5 ml of THF, and the mixture that is obtained is stirred for 20 hours at room temperature. After the further addition of 32 mg (0.32 mmol) of 2-oxopiperazine, stirring is continued for 5 hours at 60° C. The crude product is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). The title compound is obtained in a quantitative yield.
Reaction SMILES: CCCCCCCC.[CH:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[Cl-:17].[CH:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][P+:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCCCCCCC
Product: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Yield: 45 %

Procedure:
A large round-bottom flask was obtained and into this flask was charged 150 ml (102.4 g) n-octane having 99% purity, 84.6 g para-isopropylbenzyl chloride and 111.5 g triphenylphosphine. The reaction solution was heated to 95°-100° C. and maintained at that temperature for approximately 29 hours. At that time the heat was turned off and the reaction solution was cooled and charged with 197.5 methyl alcohol to dissolve the suspended solids. The methanol solution was then washed twice with 50 ml of octane each time. The octane was decanted off, leaving 383.7 g of a methyl alcohol solution of 45% para-isopropylbenzyl triphenylphosphonium chloride in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a −40° C. mixture of N-(4-chlorophenyl)-2,2-dimethylpropanamide (4.0 g, 18.9 mmol) and anhydrous tetrahydrofuran (38 ml), n-butyllithium (1.6M, 45.2 mmol) was added under nitrogen atmosphere. The reaction was stirred for 30 minutes at −40° C. and allowed to warm to 0° C. where upon the yellow homogenous mixture turned gradually darker to a deep yellow color. After 30 minutes of stirring at 0° C., the reaction was cooled to 40° C. Ethyl trifluoroacetate (6.1 g, 43.5 mmol) was added to the mixture and allowed to warm to room temperature overnight. The reaction was quenched with water (100 ml) and saturated aqueous ammonium chloride solution (80 ml). The aqueous layer was extracted with ethyl acetate (3×75 ml). Combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a dark yellow oil. Flash chromatography on silica gel (0-50% ethyl acetate/hexanes) afforded N-[4-chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethyl-propanamide. 1H NMR (CDCl3, 400 MHz) δ 11.15 (s), 8.89 (d, J=9.2 Hz, 1H), 7.92 (m, 1H), 7.65 (dd, J=2.4 and 9.2 Hz, 1H), 1.36 (s, 9H). MS (Electrospray): m/z 308.0 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:37]2[C:32]([CH:33]=[N:34][C:35](O)=[N:36]2)=[CH:31][CH:30]=1>>[N:15]1[CH:16]=[C:17]([NH:20][C:35]2[N:34]=[CH:33][C:32]3=[CH:31][CH:30]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[N:37]3[N:36]=2)[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4CCNCC4)nc3)nn12

Procedure:
This example was prepared by using 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (WO2006/047277) and 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.0 (s, 1H), 8.8 (s, 1H), 8.6 (m, 1H), 8.3 (m, 1H), 8.1 (d, J=8.5 Hz, 1H), 7.7 (d, J=7.5 Hz, 1H), 7.5 (t, 1H), 7.2 (m, 2H), 7.1 (t, 1H), 7.0 (m, 2H), 3.8 (s, 3H), 3.4 (m, 2H), 3.0 (m, 3H), 2.0 (m, 2H), 1.85 (m, 2H); LC/MS (ESI+): 401 (M+H).
Reaction SMILES: FF.[NH2:3][C:4]1[N:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1.Cl[CH:15]([F:17])[F:16]>>[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH:15]([F:17])[F:16])[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: FC(F)Cl
Agent: FF
Product: COc1cc(OC(F)F)nc(N)n1
Yield: 10 %

Procedure:
Because of the difficulty of handling fluorine, which is extremely reactive, non-selective and toxic, to date no methods for the direct fluorination of alkoxypyrimidines have been disclosed. Trifluoro- and chlorodifluoromethoxypyrimidines have not been disclosed either. Difluoromethoxypyrimidines have been obtained by a circuitous route, for example by ester cleavage of 2-amino-4,6-dimethoxypyrimidine to give the corresponding 4-hydroxy compound and subsequent reaction with chlorodifluoromethane to give 2-amino-4-difluoromethoxy-6-methoxypyrimidine in 10% yield (EP-A-70,804, Example 6). Since the starting material is prepared from trichloropyrimidine by reaction with ammonia and methanol, and then the methyl group has to be eliminated again, this is not an economic route. Direct reaction of 2-amino-4,6-dihydroxypyrimidine with chlorodifluoromethane yields the corresponding 4,6-bis(difluoromethoxy) compound in 6.4% yield (EP-A-70,804, Example 3). Finally, special safety measures are required when handling harmful chlorodifluoromethane in order to prevent escape into the atmosphere.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([CH3:30])[CH:29]=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>CN(C=O)C.O>[CH3:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3,5-dimethylphenyl)acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. The final product has about 0.7 equivalent of DMF. LC/MS (ES) m/z=413.3 [M+H]+1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 6H), 3.23 (s, 2H), 3.79 (s, 2H), 3.93 (s, 3H), 4.21 (s, 2H), 6.88-6.95 (m, 3H), 7.45 (s, 1H), 7.49 (s, 1H), 8.20 (d, J=8.34 Hz, 1H), 8.24 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C1COCC1.O>[Cl:15][C:14]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:24]([F:25])=[C:18]([C:17]([F:27])([F:16])[F:26])[CH:19]=2)[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Temperature: 2.5 °C
Yield: 27.5 %

Procedure:
Potassium carbonate (2.76 g, 20 mmol) was added to a solution of cyanuric chloride (II) (1.84 g, 10 mmol) in THF (30 mL) and the mixture cooled to 0-5° C. in an ice bath. 3-Trifluoromethyl-4-fluoroaniline (XVI) (1.79 g, 10 mmol) was added dropwise with stirring. The mixture was stirred for 16 h, diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extract was rinsed with brine (20 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography (silica gel; EtOAc/hexane (1:4)) to afford 4,6-dichloro-N-(3-trifluoromethyl-4-fluorophenyl)-1,3,5-triazine-2-amine (XVII) as an off-white solid (0.9 g, 19% yield): m.p. 114-117° C.; 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.86 (m, 2H), 7.65 (bs, 1H), 7.27 (t, 1H); ESI/MS 326 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:9](=[O:18])[N:8]([CH2:19][CH3:20])[C:7]=2[N:6]=[C:5]1[Cl:21])C=C.N1CCOCC1>C1COCC1.CS(C)=O.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>[Cl:21][C:5]1[NH:4][C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:9](=[O:18])[N:8]([CH2:19][CH3:20])[C:7]=2[N:6]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: CCn1c(=O)n(CCCO)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 7-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (3.8 g, 12.18 mmol) in THF (40 mL) and DMSO (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (800 mg, 0.693 mmol) and morpholine (5.4 mL, 62.07 mmol). The reaction was degassed and refilled with nitrogen 3 times. The reaction was stirred at room temperature overnight. The mixture was poured into water (20 mL) and ethyl acetate (100 mL). The solid precipitate was collected, washed with ethyl acetate, and dried under vacuum to give 8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.2 g, 66.4% yield) as grey solid. LCMS retention time 0.404 min; LCMS MH+ 273.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].Cl.CCOC(C)=O.CN1CCOCC1.[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([O:77]N1C(=O)CCC1=O)=O>>[N:73]1([C:88]([O:90][CH2:91][C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)=[O:89])[CH2:87][CH2:86][CH2:85][C@H:74]1[C:75]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+:34]([O-:36])=[O:35])=[O:25])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:77]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 0.68 g of Boc-Asn-Ser(Bzl)-Pip-Arg(NO2)-OBzl, 3 ml of 4N HCl-AcOEt, 0.14 ml of NMM and 0.32 g of Z-Pro-OSu in the same manner as in Example 12-(2).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@@H:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[NH2:42][C:43]1[N:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52](O)=[C:51]([F:56])[CH:50]=2)=[CH:45][N:44]=1>O1CCCC1>[NH2:42][C:43]1[N:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([O:32][CH:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:51]([F:56])[CH:50]=2)=[CH:45][N:44]=1
Reactant: Nc1ncc(-c2ccc(O)c(F)c2)cn1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2cnc(N)nc2)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of triphenylphosphine (0.315 g, 1.2 mmol) in tetrahydrofuran (THF, 5.0 mL) was added diethyl azodicarboxylate (0.19 mL, 1.2 mmol) and tert-butyl(S)-2-hydroxypropanoate (292 mg, 2 mmol) followed by 4-(2-aminopyrimidin-5-yl)-2-fluorophenol (0.20 g, 1.0 mmol) at RT (RT) under nitrogen. The mixture was stirred overnight at RT, evaporated and the residue was purified by chromatography on silica gel to afford the desired product (0.24 g, 72%). LCMS: (M+H)=334. 1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([C:21]([CH3:24])=[N:22][N:23]=2)[N:8]=[C:9]([N:11]([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:10]=1)=[O:4].[Li+].[OH-]>CO>[CH3:24][C:21]1[N:7]2[N:8]=[C:9]([N:11]([CH3:20])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2=[N:23][N:22]=1
Reactant: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc2c(C(=O)O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of (S)-methyl-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 1.22 mmol) in MeOH (15 mL) was added a 1M aqueous solution of LiOH (3.66 mL, 3.66 mmol). After 30 min, the organic solvent was removed under reduced pressure, and the pH of the aqueous layer was adjusted to pH=3 with 2N HCl, extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated to give the (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (325 mg, 85%). 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.29-7.42 (m, 5H), 5.83-5.85 (s, 1H), 2.98 (s, 3H), 2.70 (s, 3H), 1.70 (d, J=6.6 Hz, 3H), LRMS [M+H]+: 311 m/z.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[OH:22][N:23]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.N1C=CC=CC=1.[C:65]1([CH2:75][NH2:76])[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[OH:22][NH:23][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:76][CH2:75][C:65]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:68]=[CH:67][CH:66]=2)=[O:12])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: NCc1cccc2ccccc12
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NO)c1ccc(C(=O)NCc2cccc3ccccc23)cc1

Procedure:
1 eq of Wang-O—NH2 is shaken with 11 eq of terephthalic acid, 5.5 eq N,N′-diisopropylcarbodiimide, 5.5 eq 1-hydroxybenzotriazole and 25 eq diisopropylethylamine in DMF for 4 h at 25° C. After that, the resin is washed with DMF (5 times), MeOH (3 times), THF (3 times), CH2Cl2 (3 times) and diethylether (3 times). The resin is then shaken with 5 eq pentafluorophenyl trifluoroacetate and 10 eq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2Cl2 (2 times), followed by diethylether (2 times). The resin is then shaken with 5 eq of naphtalenemethylamine, 10 eq of diisopropylethylamine and leq of 1-hydroxybenzotriazole. It is then shaken with 5 eq pentafluorophenyl trifluoroacetate and 10 eq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2Cl2 (2 times). To liberate the product from the solid support, the resin is shaken with 50% TFA in dry CH2Cl2 with 5% triisopropylsilane added at rt for 1 h. The liquid phase is filtered, the resin washed with CH2Cl2 (3 times), and the combined filtrates are evaporated. The crude product is dissolved in tert-butanol/H2O (80:20) and freeze-dried. To neutralize any remaining TFA, 100 μL of a 25% NH4OH-sol is added and freeze-dried, again. The remaining solid is purified by preparative LC-MS to N-hydroxy-N′-naphthalen-1-ylmethyl-terephthalamide, MS (APCI): 321.1 (M+1)
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:11].N.[C:16](O)([CH3:19])([CH3:18])[CH3:17]>O.C1(C)C=CC=CC=1>[CH3:17][C:16]([NH:2][C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:11])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: O=S(=O)(O)O
Reactant: Cc1cccnc1C#N
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccnc1C(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A suspension of 2-cyano-3-methyl pyridine (400 g; 3.4 mol) in 800 mL of t-butanol was heated at 70° C. Concentrated sulfuric acid (400 mL) was added over 45 min. The reaction was complete after a further 30 min. at 75° C. The reaction mixture was diluted with water (400 mL) and toluene (600 mL) and brought to pH 10 with concentrated aqueous ammonia. The temperature was kept at 50°-55° C. during work-up. The toluene phase was separated, the aqueous layer extracted again with toluene and the combined toluene phases were washed with water. Removal of the toluene yielded 633 g (97%) of crystalline N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide: m.p. 56°-58° C.; NMR 9200 MHz, CDCl3)δ1.52 (s,9H); 2.75 (s,3H); 7.25 (dd,1H, J=7.5, 5 Hz); 7.58 (dd,1H, J=7.5, 1.2 Hz); 8.08 (br s, 1H); 8.40 (dd,1H, J=5), 1.2 Hz); mass spectrum, m/e (rel intensity) 192M+ (12), 177 (49). Anal. Calcd for C11H16N2O: C,68.68; H, 8.13; N,14.40. Found: C,68.71; H,8.39; N,14.57.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[N:10](S(C3C=CC=CC=3)(=O)=O)[C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2N(S(C3C=CC=CC=3)(=O)=O)C3C=C(C(=O)C4C=CC(Cl)=C(S(=O)(=O)N)C=4)C=CC=3C=2C1)=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1CO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(c3cc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)ccc3n2S(=O)(=O)c2ccccc2)C1
Agent: CCOC(=O)N1CCc2c(c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3n2S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCC1CCCO1
Solvent: O
Product: CCOC(=O)N1CCc2[nH]c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3c2C1
Temperature: 140 °C

Procedure:
A mixture of 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (1 g) is dissolved in 5 mL of tetrahydrofuran-methanol-water (10:10:1) and treated with 0.344 g of potassium carbonate. The reaction mixture is heated at 140° C. for 15 min (microwave irradiation), filtered and concentrated. The residue is purified on reverse phase HPLC to give pure 8-(4-chloro-3-sulfannoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); and 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); both as yellow syrups. Both isomers are separated by HPLC (Chiracel OD-H 250-4.6 mm, flow 1 ml/Min, UV 235 nM, gradient hexane-ethanol 70-30). The retention times are 6.91 min for 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 10.20 min for 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([NH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:15])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)CCCl)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 3-chloropropionyl chloride (32.7 g) in methylene chloride (40 ml) was added dropwise to stirred solution of (±) 1-(4-chlorophenyl)ethylamine (40 g) in dichloromethane (260 ml) with triethylamine (28.4 g) over 45 minutes at 0°-5° C. The temperature was allowed to rise to 25° C. and the mixture stirred for a further 2 hours. The cooled reaction mixture was washed with saturated aqueous sodium bicarbonate (260 ml). The organic layer was separated, dried and filtered and the filtrate evaporated. The residue was triturated with petrol, collected by filtration and recrystallised from ethyl acetate to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]propionamide, m.p. 86°-91° C. This product was obtained as a mixture with N-[1-(4-chlorophenyl)ethyl]acrylamide but was sufficiently pure for synthetic purposes. The acrylamide does not react and was removed on work-up in the next stage.