Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]([C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:20])[Cl:21])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.75 h

Procedure:
The t-Boc group of 1 g (2.2 mmol) of Boc-Asp(OBzl)-OTce is deprotected using 50 ml of 50% TFA in DCM, and the reaction mixture is stirred for 45 minutes. Volatile compounds in the reaction mixture are removed by rotary evaporator under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([O:16][CH3:17])[C:5]([Cl:18])=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:8]([C:7]1[C:6]([O:16][CH3:17])=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=1)(=[O:31])=[O:30])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1c(Cl)ccc(N)c1C(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1c(Cl)ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)c1ccccc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 131 mg of ((6-Amino-3-chloro-2-methoxy-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 3.74 (s, 3H), 6.73 (d, 1H, J=2.8 Hz), 7.16 (dd, 1H, J=9.2 Hz, 3.2 Hz), 7.33 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=6.0 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.68 (d, 1H, J=9.2 Hz), 8.82 (d, 2H, J=6.4 Hz), 9.38 (s, 1H). MS: m/z 458.1 (M++1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:35])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][C:23]4[C:28]([C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:16]=3)[CH:11]=2)[C:6]([CH3:37])([CH3:36])[CH2:5]1)(=O)C>C(O)C>[CH3:36][C:6]1([CH3:37])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:35])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][C:23]4[C:28]([C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:16]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3ccc(F)c(Nc4ncccc4-c4ccncn4)c3)cc21
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3ccc(F)c(Nc4ncccc4-c4ccncn4)c3)ccc21
Temperature: 47 °C

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-4-fluoro-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-benzamide (137 mg, 0.28 mmol, Example Norman) was dissolved in 3:1 ethanol/concentrated HCl and heated under N2 at 47° C. for 20 h. After concentration, the residue was diluted with sat'd aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried with Na2SO4, concentrated, triturated with methanol, and filtered to provide yellow solid product. MS m/z=455 [M+H]+. Calc'd for C26H23FN6O: 454.51.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35][CH2:34]3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:34][S:8][C:6]3[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=3)[C:28]([OH:30])=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CSc1nnc(S)s1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(SC)s3)C(=O)O)cc2)cc1

Procedure:
Example 33 is prepared from 5-(methylthio)-1,3,4-thiadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:4][CH2:3][CH:2]([NH2:1])[CH3:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 67.1 %

Procedure:
A mixture of (S)-(+) 2-amino-1-propanol (1.04 g, 13.85 mmol), tert butyldimethylsilyl chloride (2.09 g, 13.85 mmol) and triethylamine (2 ml, 1.05 eq) was stirred in DCM overnight ca 16 h. The reaction was diluted with DCM, washed with water, satd. NH4Cl, brine, dried and evaporated to an oil. Silica gel purification of the crude using 3% MeOH/CH2Cl2 as eluent provided 2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (1.76 g, 80%); 1H NMR (300 MHz, CDCl3) 0.0 (s, 6H), 0.82 (s, 9H), 0.99 (d, J=6.5 Hz, 3H), 2.22 (bs, 2H), 2.98 (bs, 1H), 3.30 (dd, J=10 Hz, J=17.0 Hz, 1H), 3.48 (dd, J=10.0 Hz, J=4.3 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]Br)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Mg].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>[Cu](I)I.C(OP(OCC)(OCC)=O)C.C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([Si@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CBr)CC2)CC1
Agent: I[Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](CCc3ccc(F)cc3)CC2)CC1

Procedure:
6.3 g (20 mmol) of trans-1-(trans-4-n-propylcyclohexyl)-4-bromomethyl-1-silacyclohexane was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 50 mg of triethylphosphate, 10 mg of copper iodide (I) and 3.9 g (20 mmol) of p-fluorobenzyl bromide. After a conventional after treatment, 6.1 g (yield 85%) of trans-1-(trans-4-n-propylcyclohexyl)-4-(2-(4-fluorophenyl) ethyl)-1-silacyclohexane was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)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>[NH2:12][C:13]1[CH:18]=[C:17]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:16]=[CH:15][N:14]=1
Reactant: Nc1cc(Br)ccn1
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 85 °C
Yield: 109.7 %

Procedure:
5-chloro-2-hydroxyphenylboronic acid (200 mg, 1 mmol), 2-amino-4-bromopyridine (220 mg, 1.3 mmol), sodium carbonate (490 mg, 4.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (130 mg, 0.12 mmol) were all placed in a round bottom flask and 1,4-dioxane (3 mL) and water (1 mL) were added. The mixture was heated to 85° C. for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (12 g silica gel column, 0-100% v/v ethyl acetate/hexanes gradient elution) to afford the title compound (242 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[O:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:36]3[CH:37]=[CH:38][O:34][CH:35]=3)[CH:3]=2)=[O:21])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: OB(O)c1ccoc1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(-c2ccoc2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 0.0413 g, 0.07 mmol), furan-3-boronic acid (0.009 g, 0.08 mmol), Pd(PPh3)4 (0.004 g, 3.46 nmol), DME (2 ml) and Na2CO3 (2 ml, 2M) was vigorously stirred under nitrogen in a sealed vial at 80° C. for 2 h. Another portion of furan-3-boronic acid (0.005 g) and Pd(PPh3)4 (0.004 g) was added and the reaction was allowed to go for another hour. The mixture was allowed to cool, and was then partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was extracted with another portion of EtOAc (10 ml). The combined organic phases were washed with water, brine, and dried over Na2SO4. Filtration and evaporation gave a crude oil which was purified on silica (heptane:EtOAc 2:1 to 1:1 to 1:2), which after evaporation of pure fractions gave 0.023 g (62%) of the title compound as a white solid.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(Cl)cc1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 4-chloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=231 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].CN(C1CCCCC1)C1CCCCC1.I[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH:5][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:27]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Product: COC(=O)C=Cc1ccc(OC(=O)N(C)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Methylacrylate (1.2 mmol), N-methyldicyclohexylamine (1.2 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 70% yield as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[C:37]([N:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([N:41]1[CH2:46][CH2:45][CH:44]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][N:7]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH:3]=2)[CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CC(C)(C)N1CCC(=O)CC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CCN(C(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 7-[(1-tert-butylpiperidin-4-yl)amino]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and the 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) by a procedure analogous to that described in EXAMPLE CCC18, STEP A. Mass spectrum (ESI) 677.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][OH:5]
Reactant: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (3.1 g) and triethylamine (1.3 cc) in anhydrous pyridine (62 cc) is treated with hydrogen sulphide. The greenish solution obtained is then stirred for 16 hours at a temperature in the region of 20° C., purged with nitrogen, poured into distilled water (500 cc) and extracted with ethyl acetate (2×250 cc). The combined organic phases are washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (4.8 g) is purified by chromatography on a column (height: 30 cm, diameter: 2.8 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (75:25 by volume) (3 liters) of ethyl acetate and cyclohexane and collecting 50-cc fractions. The combined fractions 19 to 50 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbothioamide (2.2 g) is thereby obtained in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 140 °C

Procedure:
Methyl 5-chloropyrazine-2-carboxylate (CAS no. 33332-25-1)(345.1 g) was dissolved in DMF (1.73 l). Lithium chloride (423.9 g) was added and the mixture heated to 140° C. over one hour. The mixture was evaporated, and the residue dissolved in water (3.4 l) by continued stirring. The solution was acidified by addition of 2N HCl (900 ml) and extracted into ethyl acetate (5×1.73 l). The combined organic extracts were washed with water (2×900 ml), brine (900 ml), dried (MgSO4), and evaporated to give the title compound (298.1 g). 1H NMR δ (400.132 MHz, DMSO) 8.92 (d, 1H), 9.02 (d, 1H), 13.87 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[N:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[N:8][CH:9]=2)[S:1][CH:2]=1
Reactant: c1cc2cnncc2s1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1csc2cnncc12
Temperature: 90 °C
Yield: 28.5 %

Procedure:
A solution of thieno[2,3-d]pyridazine (468.0 mg, 3.437 mmol) and sodium acetate (879.2 mg, 10.50 mmol) in acetic acid (14 mL) was charged with bromine (0.55 mL, 11 mmol) and then irradiated under microwave heating at 90° C. for 3 h. The reaction mixture was concentrated in vacuo. Purification by ISCO chromatography (1 to 15% methanol:dichloromethane) afforded 210.6 mg (27%) of the title compound as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (d, J=1.52 Hz, 1H), 9.53 (d, J=1.52 Hz, 1H), 8.51 (s, 1H); MS (ESI): 214.97, 216.92 [M+H]+; HPLC tR=2.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-:17].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 1.3 g (5.3 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of a 4 M aqueous solution of sodium hydroxide was heated at reflux for 4.5 h. The mixture was cooled to room temperature and washed with two 100-ml portions of tert-butyl methyl ether. The aqueous layer was acidified to pH 2-3 by addition of concentrated hydrochloric acid solution at 0° C. Extraction with three 100-ml portions of tert-butyl methyl ether, drying over sodium sulfate, filtration and concentration in vacuo gave 0.80 g (78%) of the crude title compound as a brown solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH:4]([CH2:24][OH:25])[CH2:3]1.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:25][CH2:24][CH:4]2[CH2:3][CH:2]([OH:1])[CH2:6][N:5]2[C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])=[CH:38][CH:37]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC(O)CC1CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC2CC(O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 16 h

Procedure:
(9H-Fluoren-9-yl)methyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (10.6 g, 31.2 mmoles) is coevaporated twice with anhydrous pyridine (50 mL each) and then dissolved in anhydrous pyridine (200 mL). The stirred solution is chilled in an ice bath, and 4,4′-dimethoxytritylchloride (11.0 g, 32.5 mmoles) is added in three approximately equal portions at thirty minute intervals. When the addition is complete, the flask is stoppered and place at 4° C. for 16 hours. The mixture is then evaporated to a thick yellow syrup, which is dissolved in toluene (100 mL), filtered and evaporated. The residue is dissolved in methylene chloride (350 mL) and washed successively with cold aqueous citric acid (10% [w/v], 150 mL), saturated aqueous sodium bicarbonate (150 mL) and saturated aqueous sodium chloride (150 mL). The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and evaporated to a yellow foam. The crude product is purified on silica gel (500 mL bed volume) eluting with ethyl acetate:hexanes:triethylamine (50:50:1 [v/v/v], 1300 mL; then 67:33:1 [v/v/v], 1800 mL), then ethyl acetate:triethylamine (99:1 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to an off-white amorphous solid which is dried well in vacuo. The yield is 17.7 g (88%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)ncc1Br
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of the compound obtained in Step C (2.2 g) in dimethylformamide (24 ml) was added N-chlorosuccinimide (1.4 g) in three portions at room temperature under argon. The reaction mixture was allowed to stir overnight at room temperature then a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g, prepared as described in WO 2009/080250) in DMF (6 ml) was added followed by triethylamine (1.43 ml) in DMF (14 ml). The reaction stirred at room temperature for 1 hour then poured into ice water. A white solid precipitated, which was filtered, washed with water and dried under vacuum to give the title product (4.1 g). 1H-NMR (CDCl3, 400 MHz): 8.60 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.40 (s, 1H), 4.20 (d, 1H), 3.85 (d, 1H), 2.45 (s, 3H),
Reaction SMILES: [N+]([N:4](CCCC)[C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[NH:4][CH2:5][CH2:18][CH2:17][CH3:16])[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: [H][H]
Reactant: CCCCN(c1cccc(C(=O)c2ccccc2)c1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 3-(nitro-4-n-butylamino)-benzophenone (5.96 g.; 0.02 mole) in ethanol (200 ml.) is added palladium on charcoal (5%; 0.1 g.). The mixture is hydrogenated until theoretical uptake of hydrogen has occurred (about three hours) and then let stand at room temperature overnight. The reaction mixture is filtered to remove the catalyst and the filtrate concentrated under vacuum to afford 4.75 g. (88.6% yield) of 3-amino-4-n-butylaminobenzophenone.