Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[C@@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[C@@H:20]([C:21](=[O:23])[NH:24][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2[nH]c3ccccc3c2C[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
1.58 g (3R)-2-BOC-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid, 0.915 g aminodiphenylmethane, 1.01 g EDC, and 0.709 g HBT are dissolved together in 6 ml DMF and 0.53 g triethylamine is added. The mixture is stirred at room temperature overnight and worked as in Example 5A to give 2.20 g (3R)-2-tert-butoxycarbonyl-3-diphenylmethylcarbamoyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C(OC(C)C)(C)C>>[NH2:9][C:8]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cccc(Cl)c1C#N
Solvent: CC(C)OC(C)C
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(Cl)cccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 6-chloro-2-(ethoxycarbonylamino)benzonitrile (step 1) and 2-bromoacetophenone. m.p.: 118-119° C. (isopropyl ether)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:30]#[N:31].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:29][N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[C:18](=[C:30]([NH2:31])[C:10]([C:11]([N:16]=3)=[O:13])=[C:2]3[NH:1][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:3]3)[CH:19]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(c2)=C(N)C(=C2Nc4ccccc4N2)C(=O)N=3)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-benzimidazol-2-ylacetate (1.1 equivalents) and 2-amino-5-(4-methylpiperazinyl)benzenecarbonitrile (1.0 equivalent) were dissolved in 1,2-dichloroethane, and then SnCl4 (11 equivalents) was added. The mixture was heated at reflux overnight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3 M) was added to the solid, and the mixture heated at 80° C. for 0.5 hours. The solid was filtered and washed sequentially with H2O, CH2Cl2, and acetone. LC/MS indicated that the product was present in the acetone layer and the solid. These fractions were combined and purified by silica gel chromatography (5-10% MeOH in CH2Cl2 with 1% Et3N) to give the desired product. LC/MS m/z 375.4 (MH+), Rt 1.65 minutes.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].C(O)(=O)C>CO>[C:67]([CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:69])=[O:68]
Reactant: O=CCCCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
80 mg (0.08 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 65.4 mg (0.5 mmol) of 6-oxohexanoic acid were combined in 9 ml of methanol and admixed with 10 μl of acetic acid and 37.4 mg (0.4 mmol) of borane-pyridine complex. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was taken up in 1:1 acetonitrile/water and adjusted to pH 2 with trifluoroacetic acid. The reaction mixture was concentrated again and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 70 mg (86% of theory) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were obtained as the trifluoroacetate.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].Cl[C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:6]=1[C:7]#[N:8].[OH2:16]>N1C=CC=CC=1>[N+:13]([C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[NH:3][N:2]=[C:7]2[NH2:8])([O-:16])=[O:1]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O
Reactant: NN
Solvent: c1ccncc1
Product: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Yield: 80 %

Procedure:
Hydrazine monohydrate (2.1 mL, 44 mmol) was added to a solution of 2-chloro-5-nitrobenzonitrile (7.30 g, 40 mmol) in pyridine (30 mL) and the mixture was heated to reflux overnight. The dark red solution was then cooled, poured into H2O and the resulting solid filtered and dried to give the title compound as a dark red powder (5.7 g, 80%). NMR 1H NMR (400 MHz, DMSO-D6) δ ppm 8.95 (d, J=2.0, 1H), 8.06 (dd, J=9.2, 2.0, 1H), 7.34 (d, J=9.2, 1H), 5.98 (br s, 2H) MS m/z 179.0 [M+H]+
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[CH2:22]1
Reactant: COc1ccc(C2CCCNC2)cc1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(4-methoxyphenyl)piperidine.HCl (38 mg, 0.17 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 3 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 18 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[S:36])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=CC(=O)N2CCNCC2)c2ccc(OC)cc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C(=CC(=S)N2CCNCC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
1.155 g of the 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine [prepared as described in step (a) above] were dissolved in 12 ml of benzene, and the resulting solution was heated under reflux for 2 hours with 1.326 g of Lawesson's Reagent. At the end of this time, the reaction mixture was cooled to room temperature, after which it was poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through 30 g of silica gel eluted with a 19:1 by volume mixture of methylene chloride and methanol, to give 1.177 g of 1-[3,3-bis(4-methoxyphenyl)thioacryloyl]piperazine as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH:17][NH2:18])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:17][N:18]=2)[N:3]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1ccc2nnc(-c3ccccc3)n2n1
Yield: 55.3 %

Procedure:
3,6-Dichloropyridazine (20 g, 134 mmol) was suspended in xylene (200 ml) with benzoylhydrazine (20.1 g, 1.1 mol eq) and triethylamine hydrochloride (20.3 g, 1.1 mol eq) and the reaction mixture was heated under reflux for 2 hours. The solvent was removed under high vacuum and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to give the required product (17.1 g mp=199° C.). 1H NMR (250 MHz, CDCl3) δ7.16 (1 H, d, J=9.7 Hz), 7.53-7.61 (3 H, m), 8.16 (1 H, d, J=9.7 Hz), 8.44-8.50 (2 H, m); MS (ES+) m/e 231 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1.P(Br)(Br)[Br:16].N>O>[Br:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1
Reactant: BrP(Br)Br
Reactant: Clc1ccc(-c2cncc(Cl)n2)cc1
Agent: N
Solvent: O
Product: Clc1ccc(-c2cncc(Br)n2)cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-chloro-6-(4-chlorophenyl)pyrazine (2.35 g, 10.4 mmol), was added phosphorus tribromide (17 mL) and the mixture heated at reflux for 6 h under nitrogen. The reaction mixture was cooled to room temperature prior to pouring carefully into iced water (600 mL) the resulting mixture was adjusted to pH 6–7 using aqueous ammonia and extracted with diethyl ether (2×250 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo. The reaction had not gone to completion so the residue was treated with added phosphorus tribromide (17 mL) and heated at reflux for a further 5 h under nitrogen. Work up as before afforded the title compound as a pale yellow solid (0.97 g).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:47])([F:46])[C@H:25]([CH3:45])[O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]([F:59])([F:58])[F:57]>>[F:57][C:56]([F:58])([F:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][C@@H:25]([CH3:45])[C:24]([F:23])([F:46])[F:47])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]3)[C:30]2=[N:35]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3[nH]nnc23)C1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3nn(Cc4ccccc4C(F)(F)F)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—{(S)-1-[5-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-acetamide and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 518.5 (MH+).
Reaction SMILES: N[S:2]([C:5]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH:20]([CH3:22])[CH3:21])[C:6]=1[C:7]([N:9](C)[CH3:10])=[O:8])(=[O:4])=[O:3].C(C1C(OC)=C(OC)C=C2C=1C(=O)NS2(=O)=O)(C)C.C1(SC[Cl:50])C=CC=CC=1.C1(SCN2C(=O)C3C(=CC(OC)=C(OC)C=3C(C)C)S2(=O)=O)C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(OCC)(=O)C.CCCCCC>[Cl:50][CH2:10][N:9]1[C:7](=[O:8])[C:6]2[C:5](=[CH:15][C:14]([O:16][CH3:17])=[C:13]([O:18][CH3:19])[C:12]=2[CH:20]([CH3:22])[CH3:21])[S:2]1(=[O:4])=[O:3]
Reactant: COc1cc(S(N)(=O)=O)c(C(=O)N(C)C)c(C(C)C)c1OC
Reactant: ClCSc1ccccc1
Agent: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CSc1ccccc1)S2(=O)=O
Agent: COc1cc2c(c(C(C)C)c1OC)C(=O)NS2(=O)=O
Solvent: CCOC(C)=O
Solvent: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Product: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CCl)S2(=O)=O
Yield: 85 %

Procedure:
By the method of Example 22A 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N,N-dimethylbenzamide (10.75 g) was prepared and cyclized to 4-isopropyl-5,6-dimethoxysaccharin (mp 186°-188° C. from ether-hexane), phenylthiomethylation of part (5 g) of which with chloromethyl phenyl sulfide (2.48 mL) gave 2-phenylthiomethyl-4-isopropyl-5,6-dimethoxysaccharin (4.07 g), reaction of which with sulfuryl chloride (three molar equivalents) gave 2-chloromethyl-4-isopropyl-5,6-dimethoxysaccharin, 85% yield, mp 117°-119° C. from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[O:14][CH2:15][C:16](=[O:23])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1.N1CCCCC1>CC(O)C>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:15]2[O:14][C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:26]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OCC1=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 21.6 %

Procedure:
To a solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.010 g, 0.031 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0042 g, 0.029 mmol) in 2-propanol (0.3 mL), piperidine (0.00028 mL, 0.0028 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0029 g, y. 22%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:11](C(OC)=O)=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22](O)=[O:23].S(Cl)(Cl)=O.ClCC1C=CC(C(Cl)=O)=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([F:18])[CH:20]=1)=[CH:8][NH:9]2)=[O:4]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: COC(=O)c1ccc(C(=O)OC)c2[nH]ccc12
Agent: O=C(Cl)c1ccc(CCl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C(=O)c3ccc(C)c(F)c3)c12

Procedure:
The desired compound was prepared according to the method of Example 90, step 2, except substituting 4-methoxycarbonylindole for 4,7-dimethoxycarbonylindole, and substituting 3-fluoro-4-methylbenzoyl chloride, prepared by reaction of 3-fluoro-4-methylbenzoic acid with thionyl chloride, for 4-chloromethylbenzoyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:16])[CH3:2].[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:13][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([F:12])[CH:9]=1)[N:3]([CH2:1][CH3:2])[C:4](=[O:16])[CH2:5]2
Reactant: CCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCN1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (3.84 g, 68.7 mmol) is added in small portions to 1-ethyl-7-fluoro-5-nitro-1,3-dihydro-indol-2-one (3.85 g, 17.2 mmol) and ammonium chloride (8.94 g, 171 mmol) in ethanol (150 ml) and water (75 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 30 min, cooled to room temperature, and diluted with dichloromethane (600 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a yellow solid. HPLC r.t. 2.60 min; MS for C10H11FN2O m/z 195.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1
Reactant: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (3.72 g, 9.70 mmol) in dichloromethane (25 mL). Add cold trifluoroacetic acid (30 mL, 44.2 g, 388 mmol, 40 eq.). Stir for 1 hr. Partition the crude reaction mixture between aq. 5N NaOH and dichloromethane. Separate the layers (pH aqueous layer=14). Extract the aqueous layer with dichloromethane (2×50 mL). Combine organic layers, dry over anhydrous Na2SO4, filter and concentrate to obtain the title preparation (2.76 g, 100% yield). LC MS (ES): m/z=285.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.C(Cl)CCl.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:38][CH2:37][CH2:36][C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: NCCc1ccncc1
Agent: Cn1ccnc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)NCCc4ccncc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol), 2-(pyridin-4-yl)ethanamine (50 mg, 0.41 mmol), EDC (50 mg, 0.26 mmol) and 1-methyl-1H-imidazole (50 mg, 0.61 mmol) in 25 mL of DCM was stirred at room temperature overnight. Excess of DCM was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)piperidine-3-carboxamide (25 mg, 39%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 9.64 (s, 1H), 8.85 (s, 1H), 8.46-8.44 (m, 2H), 8.02-8.01 (m, 1H), 7.71-7.69 (m, 1H), 7.33-7.21 (m, 3H), 6.92 (d, 1H, J=9.0 Hz), 4.64-4.63 (m, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 3.35-3.30 (m, 2H), 2.98-2.91 (m, 2H), 2.77-2.75 (m, 2H), 2.51 (brs, 1H), 1.82-1.42 (m, 4H). LC-MS: 520 [M+H]+, 260 [M/2+H]+, 518 [M−H]−, tR=1.29 min. HPLC: 97.55% at 214 nm, 97.72% at 254 nm, tR=3.51 min.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.Br[CH2:38][C:39]#[N:40]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][CH2:38][C:39]#[N:40])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: N#CCBr
Product: CC(OCC#N)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 8 %

Procedure:
In analogy to Example 2, 250 mg (0.39 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using bromoacetonitrile and, after workup and purification, 16 mg (8%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]2[S:17][C:16]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.[NH:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28].[CH3:33]CN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC(O)=O.C(Cl)Cl>[CH3:33][O:31][C:30](=[O:32])[CH2:29][N:27]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:16]2[S:17][C:13]([CH2:12][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]([CH3:11])[CH3:10])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)[CH3:28]
Reactant: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)s1)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CN(C)Cc1ccc(-c2ccc(CN(c3ccc(F)cc3)C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of the product of Step B (0.09 g, 0.26 mmol) and sarcosine hydrochloride (0.07 g, 0.5 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.1 ml) and 10 drops of AcOH, followed by NaBH(OAc)3 (0.11 g, 0.51 mmol). The mixture was stirred overnight at room temperature and diluted to 20 ml with CH2Cl2. The organic layer was washed with NaHCO3 solution, H2O and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.113 g, 100%) as creamy paste. 1H-NMR (CDCl3) 7.47 (d, 2H, J=8.19 Hz); 7.28 (d, 2H, J=8.18 Hz); 7.10 (d, 1H, J=3.62 Hz); 6.88-6.85 (m, 3H); 6.85-6.77 (m, 2H); 4.44 (s, 2H); 4.07-3.98 (m, 1H); 3.69 (s, 3H); 3.24 (s, 2H); 2.37 (s, 3H); 1.21 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.Cl.Cl[CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][CH2:31][O:21][C:17]1[CH:16]=[C:15]([S:14][C:11]2[CH:10]=[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Reactant: CN(C)CCCCl
Agent: Cl
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCCN(C)C)c3)cc2Oc2ccccc2)n1

Procedure:
Prepared according to the method of Example 60 using 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 9.55 (s, 1H), 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.38 (m, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H), 1.44 (m, 2H); Mass spectrum (esi) m/z=493.1 (M+H).