Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:15][C:16]1[C:17](=[O:26])[C:18](=O)[C:19]=1[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])CCC>O1CCCC1>[C:21]([NH:20][C:19]1[C:16](=[O:15])[C:17](=[O:26])[C:18]=1[NH:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[Cl:1])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2cc(Cl)ccc2Cl)c(=O)c1=O
Yield: 52.1 %

Procedure:
Employing the procedure of Example 2, Step 4, and a reaction period of 23 hours, 2,5-dichlorobenzylamine (0.88 g, 5 mmol) and 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1. 13 g, 5 mmol) in tetrahydrofuran (15 mL ) were converted to 1.52 g of a cream-colored solid. Recrystallization of this material from acetonitrile (twice) and from methanol provided 0.853 g of the tide compound as a white solid: mp 236° C. (softens 216° C.). MS (m/z) 326/328/330 (M+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH2:20][C:21](OCC)=[O:22])[N:19]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH2:20][CH2:21][OH:22])[N:19]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
Ethyl 2-(2-(4-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)acetate (1.20 g, 3.23 mmol) in THF was added to a solution of 1.0 M lithium aluminum hydride (9.69 mL, 9.69 mmol) in ether and THF (50 mL) at 0° C. The reaction mixture was stirred for 40 minutes, and cooled while carefully quenching with an excess of sodium sulfate decahydrate. A small amount of anhydrous magnesium sulfate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered, and the cake was washed with THF several times. The combined filtrates were concentrated and the residue was recrystallized from 3:1 ethyl acetate:hexanes (50 mL). The crystals were filtered, washed with hexanes and dried to afford 2-(2-(4-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)ethanol (0.501 g, 47.1% yield) as light pink crystals/needles. 1H NMR (d6-DMSO) δ 11.11 (s, 1H), 8.08 (d, 1H), 7.53-7.61 (t, 6H), 6.73 (s, 1H), 6.57 (s, 1H), 6.56 (m, 1H), 4.58 (t, 1H), 3.65 (m, 2H), 2.69 (t, 2H).
Reaction SMILES: Cl.[Cl:2][CH:3]([CH2:6][CH2:7][CH2:8][Cl:9])[CH2:4][NH2:5].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([NH:5][CH2:4][CH:3]([Cl:2])[CH2:6][CH2:7][CH2:8][Cl:9])(=[O:12])[CH3:11]
Reactant: NCC(Cl)CCCCl
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)NCC(Cl)CCCCl

Procedure:
acetylizing the 2,5 dichloropentylamine hydrochloride with acetyl chloride to form N-acetyl-2,5-dichloropentylamine,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:38])[F:39])=[CH:33][CH:32]=4)(=[O:36])=[O:35])=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 298 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 4-trifluoromethyl benzene sulfonyl chloride. The compound of example 298 was used directly without isolation, for the preparation of compound of example 299.
Reaction SMILES: CSC.[N+:4]([C:7]1[CH:24]=[CH:23][C:10]([CH:11]=[N:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[C:25]1([CH:31]=[N+]=[N-])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.C(OC)(C)(C)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[N+:4]([C:7]1[CH:24]=[CH:23][C:10]([CH:11]2[CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CSC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C(c3ccccc3)C2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To a stirred solution of dimethylsulphide (5 μl, 0.07 mmol), rhodium (II) acetate (2 mg, 0.005 mmol) and N-(4-nitrobenzylidene)toluene-p-sulphonamide (102 mg, 0.33 mmol; J. C. S. Perkin I (1981) 2435-2442) in dichloromethane (2 ml) was added phenyldiazomethane (prepared as in Example 36; 8.11 ml of a 0.074M solution in t-butylmethylether) over a period of 12 hours. Upon completion of the addition the solvent was removed in vacuo and the residue was chromatographed using silica gel elating with 15:85 ethyl acetate:petrol to give the title compound as a mixture of trans and cis isomers. Trans isomer (48 mg, 37%) δH (CDCl3) 8.10-8.19(2H,m), 7.53-7.64(4H,m), 6.95-7.41(7H,m), 4.27(1H,d,J=6 Hz), 4.16(1H,d,J=6 Hz), 2.36(3H,s)ppm. Cis isomer (9 mg; 7%) δH (CDCl3) 8.23-8.33(2H,m); 7.15-7.60(11H,m), 4.13(1H,d,J=2 Hz) 3.87(1H,d,J=2 Hz) 1.68(3H,s)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:36]=[CH:35][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C(C)(C)C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:33]#[N:34])=[CH:13][CH:12]=2)=[O:10])=[N:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:33]#[N:34])=[CH:35][CH:36]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)cn4)cc3)c(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(Cl)cn3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 70.9 %

Procedure:
tert-Butyl 7-(4-(5-chloropyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (4 mg, 0.0079 mmol) was diluted with DCM (500 μL) and TFA (500 μL). After stirring for 2 hours, the reaction was concentrated and placed under high vacuum for 1 hour. The residue was purified by preparative TLC, eluting with 10% methanol/DCM to provide the desired product (2.5 mg, 0.0056 mmol, 70% yield) as a white solid. MS (ESI)=450.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 17 h
Yield: 92.2 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (300 mg, 1.02 mmol), phenylboronic acid (256 mg, 2.03 mmol) and tripotassium phosphate (432 mg, 2.03 mmol) were dissolved in 1,4-dioxane (6 ml), then tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.10 mmol) was added at room temperature. The solution was stirred under nitrogen atmosphere at 100° C. for 17 hours. After cooling to room temperature, aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by stirring at room temperature for 10 minutes. The insoluble matter was separated by filtration with washing with ethyl acetate, and further the aqueous layer of the filtrate was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=8:1) to obtain the entitled compound (275 mg, 92%) as a white solid.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23]N>C(O)C>[CH3:19][N:20]1[CH2:21][CH2:22][CH2:23][NH:18][C:4]1=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNCCCN
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: CN1CCCNC1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) and absolute ethanol (40 ml) was heated under reflux for 6 hours to give a solid which was recrystallised from ether to give 4-[2-(1-methylperhydropyrimidin-2-ylideneamino)phenyl]morpholine (m.p. 138°-139° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[N:13]=1.C(Cl)Cl>C(OCC)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)N=C=O
Reactant: Nc1nc2cc(Cl)ccc2s1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)NC(=O)Nc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
One part by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 2 parts by weight of 2-amino-5-chlorobenzothiazole in 100 parts by weight of methylene chloride and 50 parts by weight of ethyl ether. After stirring the reaction mixture at room temperature overnight, a product was isolated by filtration giving an 85% yield of methyl 4-(5-chlorobenzothiazol-2-yl)allophanate having a melting point of 395°.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH2:11][C:8]1[N:9]=[CH:10][C:5]2[CH2:4][CH2:3][CH2:2][O:19][C:6]=2[CH:7]=1
Reactant: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1nc(COC2CCCCO2)cc2c1CCCO2
Reaction time: 0.17 h

Procedure:
To a solution of 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one in 8 mL of tetrahydrofuran, 0.54 g of triphenylphosphine and 0.89 g of a 40% diethyl azodicarboxylate/toluene solution were added, and the mixture was stirred for 10 minutes. The solvent was distilled off under reduced pressure to obtain 7-((tetrahydro-2H-pyran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridine as a brown oily substance.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.09 min, m/z=500.3 [M+H]+, m/z=498.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.69 (m, 1H) 1.77-1.96 (m, 1H) 2.16-2.30 (m, 1H) 2.97 (dd, J=11.00, 7.09 Hz, 1H) 3.10-3.22 (m, 2H) 3.22-3.27 (m, 1H) 3.34-3.45 (m, 2H) 4.60 (br. s, 1H) 7.70 (d, J=8.80 Hz, 2H) 7.87-7.99 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.41 (t, J=2.08 Hz, 1H) 8.80 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O-])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1.[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[N:6][CH:7]=1
Reactant: Nc1ccc([O-])c([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ncc(Br)cn2)c([N+](=O)[O-])c1

Procedure:
1.94 g of 5-bromo-2-chloropyrimidine and 1.93 g of sodium 4-amino-2-nitrophenolate were dissolved in 20 ml of dimethylformamide, and reacted in the atmosphere of nitrogen gas at 150° C. for 5 hours. After the completion of the reaction, the reaction product was poured into water, and extracted with ethyl acetate. The extract layer was washed with brine and dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, whereby 1.35 g of 4-(5-bromo-2-pyrimidinyl)-3-nitroaniline having a melting point of 165° to 167° C. was obtained.
Reaction SMILES: CI.[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[NH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[N:29]([CH3:33])[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc2ncc3c(c2n1)NC(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 123.6 %

Procedure:
Methyl iodide (10.5 μL, 0.17 mmol, 1.0 eq) is added at room temperature to a stirred solution of [6-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester (70 mg, 0.17 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by cesium carbonate (55 mg, 0.17 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [6-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an orange viscous oil (89 mg, 75% yield) that is directly engaged in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([F:37])[C:18]3[N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][C:23](Br)=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:97]1[CH2:102][CH2:101][O:100][CH2:99][CH2:98]1>>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([F:37])[C:18]3[N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][C:23]([N:97]2[CH2:102][CH2:101][O:100][CH2:99][CH2:98]2)=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(Br)ccc2N3C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(N4CCOCC4)ccc2N3C(=O)OC(C)(C)C)CC1

Procedure:
To a stirred solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-fluoro-7-bromo-10-Boc-phenothiazine (1.1 g, 2.0 mmol) in toluene (10 mL) Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (31 mg, 0.018 mmol), Cs2CO3 (652 mg, 2.0 mmol) and morpholine (348 mg, 4.0 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][O:16][S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(CC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2,2-Diphenylethyl)-3(S)-hydroxymethyl-piperidine (1.01 g, 3.41 mmol) was dissolved in dry pyridine (25 mL) and tosyl chloride (0.684 g, 3.58 mmol) was added to the solution After stirring at ambient temperature for 18 hr, the solution was concentrated, the residue taken up in EtOAc, washed with sat. NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration gave the title compound without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([C:7]1[CH:8]=[C:9]([C:13]([NH:15]C(=O)C)=[CH2:14])[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4]>CO>[F:1][C:2]([F:19])([C:7]1[CH:8]=[C:9]([CH:13]([NH2:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[C:3]([F:4])([F:6])[F:5]
Reactant: C=C(NC(C)=O)c1cccc(C(F)(F)C(F)(F)F)c1
Solvent: CO
Product: CC(N)c1cccc(C(F)(F)C(F)(F)F)c1

Procedure:
To a solution of N-[1-(3-Pentafluoroethyl-phenyl)-vinyl]-acetamide (110 mg, 0.39 mmol) in methanol (10 ml) was added (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate (0.3 mg). The reaction mixture was hydrogenated with H2 at 5 bar and evaporated. The residue was dissolved in ethanol and hydrochloric acid (6 M, 0.7 ml) and the solution was refluxed for 2 days. Purification by preparative HPLC and lyophilization of the relevant fractions gave the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[F:29][CH2:30][CH:31](O)[CH2:32][F:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:29][CH2:30][CH:31]([CH2:32][F:33])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: OC(CF)CF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1OC(CF)CF)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 113.6 %

Procedure:
A solution of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine (76 mg) and diisopropylazodicarboxylate (48 mg) was refluxed overnight, concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a colorless solid (68 mg). MS (m/e): 474.1 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14](I)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[F:20][C:21]1[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:27][C:22]2[C:21]([F:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(I)cc1=O
Reactant: Oc1ncccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ncccc2F)cc1=O
Temperature: 120 °C
Yield: 52.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (0.38 g, 1 mmol) in N,N-dimethylformamide (10 mL) was treated with 3-fluoro-pyridin-2-ol (0.15 g, 1 mmol) and potassium carbonate (0.16 g, 1.2 mmol). The reaction was heated at 120° C. for 4 h and then concentrated in vacuo. The residue was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, and then concentrated in vacuo. Chromatography (1/1 ethyl acetate/petroleum ether) afforded 3-cyclopentyl-2-[4-(3-fluoro-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (0.19 g, 53%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(NS(=O)(=O)c2ccccc2)cn1)c1ccccc1
Reaction time: 4 h
Yield: 28.2 %

Procedure:
Benzenesulphonyl chloride (0.18 g, 1.00 mmol), dissolved in a small amount of dichloromethane, was added dropwise to a stirred solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.24 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in dichloromethane (10 mL). After stirring for 4 hours the solution was extracted with water and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60 followed by 50:50) yielding the title compound (108 mg, 23% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8](I)=[N:7]1.[Cu][C:29]#[N:30]>CN(C)C=O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8]([C:29]#[N:30])=[N:7]1
Reactant: N#C[Cu]
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12

Procedure:
A 5 mL microwave reaction vessel was charged with 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde (300 mg, 0.6 mmol), copper (I) cyanide (135 mg, 1.5 mmol), and N,N-dimethylformamide (4 mL). The vessel was sealed and subjected to microwave irradiation at 185° C. for 15 min. The reaction mixture was partitioned between EtOAc and water. The organic layers were washed with brine, dried over Na2SO4, and evaporated. The crude residue was purified by flash column chromatography on silica gel, eluting with EtOAc/hexanes (1:4 v/v), to afford the title compound as a white solid.