Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(F)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.21) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 497.1 [(M+H)+]; mp 256° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1.[NH3:22]>C(O)C>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1
Reactant: N
Reactant: NC(=O)CCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
To a solution of 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide (0.5 g.) in 6 M ammonia in ethyl alcohol (6 ml.) was added mercuric oxide (0.56 g.) over 5 minutes. The mixture was stirred for 1 hour and filtered. The filtrate was evaporated in vacuo to an oil which was dissolved in EtOAc. Addition of petroleum ether (b.p. 60°-80°) gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide as a crystalline solid, m.p. 128°-132°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])=O>>[CH3:27][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)O)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (34 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[F:8][C:9]([F:53])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[F:53][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29]([N:6]4[CH2:7][CH:4]([O:3][CH3:2])[CH2:5]4)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=1
Reactant: COC1CNC1
Reactant: COC(=O)CCc1ccc(OC)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(OC)c(-c2cnc(N3CC(OC)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-azetidine hydrochloride (60.4 mg, 0.488 mmol) was added into a stirred mixture of methyl 3-{3-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methoxyphenyl}propanoate (66 mg, 0.098 mmol) and triethylamine (0.068 mL, 0.488 mmol) in THF (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The yellow reaction crude was concentrated in vacuo. The resulting pot residue was purified by preparative HPLC (reverse phase, SunFire Prep C18 OBD 5 um 19×150 mm) eluting with acetonitrile/water+0.05% HCOOH (20% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min) to give a colorless glass as the titled compound. LCMS calc.=682.22. found=683.27 (M+H)+. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 7.86 (s, 1H), 7.73 (s, 2H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 5.59 (br d, J=8.0 Hz, 1H), 4.73 (br d, J=17 Hz, 1H), 4.41-4.32 (m, 3H), 4.28 (br s, 1H), 4.11-4.03 (m, 2H), 3.91 (br s, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.37 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 0.66 (br s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9]([C:24]1[CH:37]=[CH:36][C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])=[CH:26][CH:25]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 476.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:20])[CH:17]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[CH:26][CH:25]=[CH:24]4)=[O:20])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using an analogous procedure to that described in Example 4, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound; Mass Spectrum: M−H− 415.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[CH:30]1([C:33]([CH:42]2[CH2:44][CH2:43]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([SH:41])[CH:36]=2)[OH:34])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:42]1([C:33]([CH:30]2[CH2:31][CH2:32]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([S:41][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]3[C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[N:13][N:14]=[C:7]3[CH:6]=[CH:5]4)[CH:36]=2)[OH:34])[CH2:44][CH2:43]1
Reactant: OC(c1cccc(S)c1)(C1CC1)C1CC1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1cccc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)c1)(C1CC1)C1CC1
Temperature: 100 °C

Procedure:
To 7-iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (10j, 176 mg, 0.47 μmmol) in 1,4-dioxane (4.5 mL) was added iPr2NEt (0.16 mL, 0.94 mmol), and the reaction was degassed with N2 for 5 minutes. 10i (174 mg, 0.47 mmol) was added, followed by Pd2dba3 (22 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.05 mmol). The reaction was sealed and heated at 100° C. for 6 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-80% EtOAc in hexanes) to give the desired product, 10k.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg (0.21 mmol) spiro[piperidin-4,4′-pyrido[2.3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 65 mg (0.21 mmol) 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.84 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: O[CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1.C(Br)(Br)(Br)[Br:34].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Br:34][CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(CO)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CBr)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(9-(9-Hydroxy-8-methylnonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 283, step b) (100 mg), carbon tetrabromide (143 mg) and imidazole (30 mg) were dissolved in DCM (5 mL). The solution was cooled to 0° C. and a solution of triphenylphosphine (85 mg) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at this temperature for 1 hour then at room temperature for 2 hours. A further amount of carbon tetrabromide (150 mg) was added, the mixture cooled to 0° C. and triphenylphosphine (114 mg) in DCM (1 mL) added dropwise. Stirred at room temperature for 1 hour then water was added and the phases separated. The organic phase was evaporated and the product purified by silica gel chromatography eluting with 0-10% methanol in DCM to afford the subtitled compound as an orange gum. Yield 0.088 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([SH:18])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([S:18][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: S[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.27 g of a 55% w/w suspension of sodium hydride in mineral oil was suspended in 2 ml of dimethylformamide. To the suspension was added dropwise a solution of 1.210 g of dl-cis-2-benzyloxymethyl-3-mercaptotetrahydropyran (prepared as described in Preparation 16) in 5 ml of dimethylformamide, whilst ice-cooling the mixture. The reaction mixture was stirred at 60° C. for 1 hour, after which it was cooled to room temperature. A solution of 1.86 g of hexadecyl bromide in 3 ml of dimethylformamide was then added, and the mixture was stirred at room temperature for 1 hour. It was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 10:90 by volume was collected to give 2.284 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(O)C.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][CH:18]([C:17]#[N:21])[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1cccc(OCc2ccccc2)c1
Yield: 91.6 %

Procedure:
Using 1.06 g of 3-(benzyloxy)benzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 19, there was obtained 1.20 g of (3-(benzyloxy)benzyl)malononitrile (the intermediate (31)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](O)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:14])([F:15])[F:16])=[C:10]([CH2:17][OH:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-carboxylic acid (0.30 g) in tetrahydrofuran (10 ml) stirred under a nitrogen atmosphere at 0° C. was treated with a 1M solution of borane in tetrahydrofuran (10.33 ml) and the reaction stirred at room temperature for 2 hours. The reaction was cooled to 0° C.; treated with methanol (4 ml) and after 15 minutes the reaction mixture was evaporated. The residue was purified by SPE (Si cartridge) sequentially using dichloromethane, chloroform and chloroform:ether (9:1) as eluents to give the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1.[CH3:15][O:16][CH:17](Cl)[CH3:18].[OH-].[Na+]>CCCCCC>[CH3:15][O:16][CH:17]([N:12]1[C:9]([CH3:14])([CH3:8])[CH2:10][C:11]1=[O:13])[CH3:18]
Reactant: COC(C)Cl
Reactant: CC1(C)CC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(C)N1C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.3 g of triethylamine and then a mixture of 19.8 g (0.2 mole) of 4,4-dimethyl-azetidin-2-one and 43.2 g of triethylamine are added dropwise, at 0° C., to a solution of 38 g (0.4 mole) of α-chloroethyl methyl ether in 60 ml of hexane. The mixture is stirred for a further 2 hours at 0° C. and 10 ml of 50% strength sodium hydroxide solution and 20 g of powdered sodium hydroxide are added. After a further 30 minutes, the hexane solution is decanted, the deposit is rinsed with hexane and the hexane extracts are concentrated on a rotary evaporator. This yields 25.5 g (81% of theory) of 1-α-methoxyethyl-4,4-dimethyl-azetidin-2-one. 1H-NMR (CDCl3): 1.4 ppm (d); 1.5 ppm (s); 2.75 ppm (s); 3.3 ppm (s); 4.8-5.1 ppm (q).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:21]([O-:23])=[O:22])=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a vigorously stirred solution of N-(3-fluoro-4-trifluoromethyl-phenyl)-acetamide (0.663 g, 3.00 mmol) and sulfuric acid (3 mL) was added dropwise a solution of potassium nitrate (0.607 g, 6.00 mmol) and conc. sulfuric acid (3 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then slowly pipetted into ice/water with stirring. The resulting precipitate was collected and dried in vacuo to yield the titled compound (0.648 g, 81% yield) as a single regioisomer. The compound did not yield MS data. 1H NMR (600 MHz, CDCl3): 10.67 (br s, 1H), 8.86 (d, J=12.9 Hz, 1H), 8.57 (d, J=7.2 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Product: CC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Yield: 45 %

Procedure:
Compound (1) (0.00135 mol) and acetic acid anhydride (20 ml) were combined and heated to reflux for 10 minutes. The reaction mixture was then removed from the oil bath and cooled to RT. The precipitate was filtered off, yielding 0.25 g (45%) of N-(4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-acetamide (compound 22).
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].C1([Mg]Br)CC1>C1COCC1>[CH:16]1([C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:18][CH2:17]1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)[Mg]Cl
Agent: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)C1CC1
Temperature: 10 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of tert-butyl N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (2,455.3 g, 11.25 mol) in THF (9.0 L) is added 2.0M isopropylmagnesium chloride in THF (5.34 L, 10.69 mol) at −30° C. via an addition funnel over a period of 60 min such that the internal temperature does not exceed 0° C. The mixture is then warmed slowly to 10° C. and 0.5M cyclopropylmagnesium bromide in THF (27.0 L, 13.50 mol) is added via an addition funnel over a period of 1 h. The mixture is stirred at room temp 24 h. The mixture is cooled to 0° C. and quenched with 1.0M HCl to pH 5-6, then warmed to room temp and extracted with EtOAc (12 L and 10 L). The combined organic phase is washed successively with water (10 L) and brine (8 L), dried over Na2SO4, and filtered. The filtrate is evaporated under reduced pressure to afford 2.24 kg (100% yield) of the title compound as a light yellow oil which is used directly for the next step.
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=S)[CH2:10][CH3:11]>C(O)C.O>[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=[O:5])[CH2:10][CH3:11]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CCO
Solvent: O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Fumaric acid (2.7 g) is added to a solution of N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (9.5 g) in ethanol (100 cc). The solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The merigue-like yellow residue is taken up with acetic acid (200 cc). Mercuric acetate (7.3 g) is added to the solution obtained, and the mixture is stirred for 16 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with distilled water (200 cc) and filtered. The yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc) and then treated with sodium hydroxide (d 1.33) to pH 13. The aqueous phase is separated after settling has taken place and extracted with ethyl acetate (250 cc). The organic phases are combined, washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (9.2 g) is thereby obtained. This residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (95:5 by volume) of methylene chloride and methanol. The first 1,500 cc are discarded and the next 1,500 cc are concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (7.3 g) in the form of a yellow gum.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CI.[CH3:19]C(C)=O>O>[CH3:19][O:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: CC(C)=O
Solvent: CI
Solvent: O
Product: COc1ccc(C)cc1C(=O)c1ccccc1
Yield: 71.5 %

Procedure:
To a solution of 5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone and 6.67 g (47.1 mmole) methyliodide in 50 ml abs. acetone 4.50 g (32.6 mmole) potassium carbonate are added. The reaction mixture is then heated for 5 hours with recycling. Following cooling, 50 ml water and 50 ml petroleum ether (30/60) are added to the suspension. The organic phase is separated off, the aqueous phase is extracted twice with 75 ml petroleum ether (30/60) and the purified organic phase is washed twice with 50 ml 10% NaOH solution. The organic phase is then dried through magnesium sulphate and the solvent is removed. 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone are obtained.