Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29](OCC)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[N:9][CH:8]=2)=[CH:35][CH:36]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 10.22 (1H, br t, J=5 Hz), 8.58 (1H, d, J=1.2 Hz), 7.85 (2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.3 Hz), 7.01-6.98 (5H, m), 5.44 (2H, br), 4.02 (2H, s), 3.68 (2H, q, J=5.2 Hz), 3.60 (2H, t, J=5.2 Hz); 3.41 (3H, s), 3.03 (3H, s); ES+ MS: 540 (M+H+, 100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][C:25]2(C(OC(C)(C)C)=O)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]>CO>[ClH:2].[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][CH:15]([CH2:17]3)[CH2:16]1)[CH2:18]2)=[O:6]
Reactant: CC(C)(C)OC(=O)C1(CSc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CCNCC1
Agent: Cl
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(SCC2CCNCC2)ccc1Cl
Yield: 193.3 %

Procedure:
Hydrochloric acid (4N dioxane, 0.5 ml) was added to a solution of 2-chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidin-4-ylmethylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.235 g, Example 58a) in methanol (10 ml). After 24 h the reaction mixture was concentrated, then triturated with ether to give the title compound (0.20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:16]([O:15][C:13]([N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:28]1=[O:30])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.1 %

Procedure:
Part 2. To a chilled solution of methyl 3-amino-4-[(tert-butoxy)carbonylamino]benzoate (0.40 g, 1.5 mmol) in CH2Cl2 (10 mL) and triethylamine (0.21 mL, 1.5 mmol) was added a solution of triphosgene (161 mg, 0.54 mmol) in CH2Cl2 (6 mL) over 5 min. The reaction was stirred at room temperature for 2 hr, diluted with CH2Cl2, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50% ethyl acetate in CH2Cl2 as eluent to give methyl 1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.27 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]3[CH2:49][CH2:48][N:47]4[CH2:51][CH2:52][CH2:53][C@H:46]4[CH2:45]3)=[O:17])[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Reactant: C1C[C@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (S)-octahydropyrrolo[1,2-α]pyrazine (0.55 g, 4.33 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and then diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][CH:10]=2>O.Cl>[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[N:1]1
Reactant: Cc1ccccc1Nc1c(N)cnc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1-n1nnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of sodium nitrite (0.82 g, 12 mmol) in water (10 ml) was added dropwise to a stirred suspension of 3-amino-4-(2-methylphenylamino)quinoline (2.0 g,8 mmol) in 2M HCl (80 ml) at 0.5°. The solid gradually dissolved to give a pale orange solution which deposited a solid after about 1 hour. After warming to room temperature the solid was collected, washed with water and recrystallised from aqueous ethanol with charcoaling, to give the title compound as a white solid (0.55 g, 26%), m.p. 140°-142° .
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Yield: 136.1 %

Procedure:
A mixture of Toluene-4-sulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (4.47 g; 13.9 mmol; 1.0 eq.), 4-Iodo-1H-pyrazole (2.69 g; 13.9 mmol; 1.0 eq.) and cesium carbonate (6.78 g; 20.8 mmol; 1.5 eq.) was heated in DMA (50.0 mL) at 100° C. for 3 h. It was then allowed to cool to RT, diluted with EtOAc and washed with water and brine. Aqueous phases were back-extracted with EtOAc. Combined organic phases were finally dried over sodium sulfate, filtered and concentrated to give 6.32 g of a yellow oil. Recrystallisation in iPrOH afforded the title compound as a white powder (2.81 g, 61%). HPLC (Condition A): Rt 3.46 min (purity 100%). MS (ESI+): 335.1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:26])([F:25])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14]C=1C(O)=O.CN(C=O)C>CCOCC>[F:7][C:8]([F:25])([F:26])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:15]=[CH:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 115.3 %

Procedure:
Oxalyl chloride (0.64 g) in dry ether (7 ml) was added dropwise with stirring to 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoic acid (0.926 g) in dry ether (40 ml) at room temperature. A drop of DMF was added during the addition. After two hours further oxalyl chloride (0.257 g) was added and the reaction stirred for a further two hours. The organic solution was then decanted from a precipitate, and evaporated to yield 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoyl chloride as a liquid (1.136 g), which was used without purification.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15].[OH-].[Na+]>O>[Br:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: BrCCCCCCBr
Reactant: C#CCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCCCOCCCCCCBr
Reaction time: 22 h

Procedure:
A mixture of 5-hexyn-1-ol (5 g), 1,6-dibromohexane (37.29 g), TAB (1 g) and 50% sodium hydroxide solution (20 ml) was stirred under nitrogen for 22 h. The mixture was diluted with water (100 ml) and extracted with diethyl ether (2×150 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane followed by hexane:ether (95:5) gave the title compound as a colourless oil. (7.7 g), t.l.c. (hexane:ether 2:1) Rf 0.80.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.N12CCCN=C1CCCCC2.Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[S:39][CH:40]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[S:39][CH:40]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.91 g (22.12 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 150 ml of DMF. 7.44 g (66.35 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.8 g (44.24 mmol) of 4-chloromethyl-2-(4-chlorophenyl)-1,3-thiazole are then added. The suspension is stirred at RT overnight, 50 g of silica gel are added and the mixture is concentrated under reduced pressure. The substance mixture on the silica gel is purified by chromatography on silica gel (mobile phase: toluene to toluene/ethyl acetate, 1:1 mixture). This gives 5.5 g (47% of theory) of product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:22])[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][CH2:20][NH2:21])[C:13]=2[O:12][CH2:11]1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:18]2[C:13]3[O:12][CH2:11][C:10]([CH3:22])([CH3:9])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1(C)COc2c(CCN)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)COc2c(CCNc3cc(Cl)ncn3)cccc21
Temperature: 90 °C

Procedure:
As shown in step 3-vi of Scheme 3, a solution of 4,6-dichloropyrimidine (111.6 mg, 0.726 mmol), 2-(3,3-dimethyl-2H-benzofuran-7-yl)ethanamine (139 mg, 0.726 mmol), Na2CO3 (231.1 mg, 2.180 mmol) in i-PrOH (5.56 mL) was sealed in a microwave-type tube and heated at 90° C. in an oil bath for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth, the volatiles removed under reduced pressure, and the residue purified by medium pressure chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 6-chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (Compound 2006) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.25 (s, 1H), 4.20 (d, J=5.9 Hz, 2H), 4.05 (d, J=7.1 Hz, H), 3.47 (s, 2H), 2.83 (t, J=6.6 Hz, 2H), 1.50 (s, 2H) and 1.27 (s, 6H) ppm; ESMS (M+H)=304.06.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13](O)[CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH2:13][CH2:12][CH:11]=1
Reactant: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)c2ccoc2CC1
Yield: 85.3 %

Procedure:
To a mixture of 19.3 g of 4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 mL of toluene was added 100 mg of p-toluenesulfonic acid monohydrate, and the mixture was placed on a Rotovap, and the solvent was distilled in vacuo (60° C.) until a residue was obtained. The residue was chromatographed on silica (hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of 6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula Ill: R3 =H; ##STR53## R5 =2-benzofuryl) as an orange oil.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)CC[N:9]([C:19](C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:8][C:7]=2[CH:31]=1.Cl.N1C=C(CN2[C:45]3[CH:46]=[CH:47][C:48]([C:50]#N)=[CH:49][C:44]=3[CH2:43][N:42]([S:52]([CH3:55])(=[O:54])=[O:53])[C@H](CC3C=CC=CC=3)C2)N=C1>>[ClH:1].[ClH:1].[NH:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]4[CH:5]=[CH:4][CH:3]=[CH:31][CH:7]=4)=[CH:49][C:44]=3[CH2:43][N:42]([S:52]([CH3:55])(=[O:53])=[O:54])[C@H:5]([CH2:4][C:3]3[CH:19]=[N:9][CH:8]=[CH:7][CH:31]=3)[CH2:6]2)[N:15]=[CH:16]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1

Procedure:
Example 273 was prepared as a light yellow solid from D-pyridylalanine and Compound B of Example 226 using the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound C of Example 264.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]1[CH2:13][CH2:12][CH2:11][C:9]=1[N:10]=2.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]1[CH2:13][CH2:12][C:11](=[CH:21][C:20]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[C:9]=1[N:10]=2
Reactant: O=c1c2c(nc3ccc(Cl)cn13)CCC2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=C2CCc3c2nc2ccc(Cl)cn2c3=O)cc(OC)c1OC
Yield: 60.9 %

Procedure:
7-chloro-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one (4 g), prepared according to Example 1, was reacted with 3,4,5-trimethoxy-benzaldehyde (8,87 g) in methanol (160 ml) in the presence of sodium methoxide (1.65 g) at reflux temperature for 140 hours. After cooling the precipitate was filtered, washed with water until neutral and crystallized from CH2Cl2 /methanol to give 4.4 g of 7-chloro-3-(3,4,5-trimethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one, m.p. 222°-223° C., NMR (CDCl3) δ ppm: 3.13 (br s) (4H, cyclopentane protons), 3.95 (br s) (9H, --OCH3), 6.82 (s) (2H, phenyl protons), 7.42 (br s) (1H, =CH--), 7.58 (d) (2H, C-5 and C-6 protons), 9.02 (t) (1H, C-8 proton).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH2:15][CH3:16])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:15]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH:21]=[CH:25][CH:24]=[CH:23]3)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:6](=[O:18])[C:7]1=[O:17])[CH3:16]
Reactant: CCn1c(=O)c(=O)[nH]c2cc(N)c([N+](=O)[O-])cc21
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(=O)[nH]c2cc(-n3cccc3)c([N+](=O)[O-])cc21
Yield: 374.7 %

Procedure:
4.0 g (16 mmol) of 6-amino-1-ethyl-7-nitro-2,3(1H,4H)-quinoxalinedione, 2.4 g (18 mmol) of 2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap for 3 h. The mixture was then concentrated under reduced pressure, and the residue was treated with methanol. The precipitate was filtered off with suction to yield 18 g (3%) of the product. Melting point 248°-250° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>ClCCl>[CH3:23][S:20]([O:10][CH2:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:22])=[O:21]
Reactant: OCCCN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask was charged with 3-morpholinopropan-1-ol (1.0 g, 6.9 mmol), DIEA (2.4 mL, 14 mmol) and dichloromethane (100 mL). Mesylchloride (0.64 mL, 8.3 mmol) was added in a drop wise fashion to the dichloromethane mixture and the reaction mixture was stirred at room temperature for 15 hours. Concentration of the reaction mixture gave rise to a quantitative yield of 3-morpholinopropyl methanesulfonate, which was used in the next step without any further purification.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31]>[Zn].C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCc1ccc(C=O)cc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C=C(Br)Br)cc1
Reaction time: 2 h

Procedure:
A mixture of 4.94 g. (0.015 mol.) of carbon tetrabromide, 3.90 g. (0.015 mol.) of triphenylphosphine and 0.975 g. (0.015 g.-atom) of zinc in 25 ml. of carbon tetrachloride is stirred at 25° for 24 hours. A solution of 1.0 g. (7.45 mmol.) of p-ethylbenzaldehyde in 10 ml. of methylene chloride is added and the reaction mixture is stirred an additional 2 hours. Petroleum ether (140 ml.) is added to the mixture, the organic layer is decanted and the residue is extracted with 1:4 methylene chloride-petroleum ether. The combined organic solutions are concentrated under reduced pressure to give 1,1-dibromo-2-(4-ethylphenyl)ethylene.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.[CH2:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:25][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1
Reactant: CC(C)(C)CN
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(Cl)ncn2)c1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)ncn2)c1
Temperature: 110 °C
Yield: 95.4 %

Procedure:
To a solution of 3-(6-chloro-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (0.4 g, 1.44 mmol) in DMSO (3 mL), neopentylamine (0.4 mL, 3.39 mmol) was added. The resulting solution was heated at 110° C. for 4 days. The product was purified by silica gel column chromatography using ethyl acetate as eluent to afford the product (0.45 g, yield 99%). MS (m/z): 328 (M+H).
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12]>C(#N)C.O>[Cl:4][C:5]1[C:6]2[N:12]=[C:2]([NH2:1])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N#CBr
Reactant: Nc1cccc(Cl)c1N
Solvent: O
Solvent: CC#N
Product: Nc1nc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide was added to a solution of 3-chlorobenzene-1,2-diamine (0.81 g, 0.570 mmol) in acetonitrile (10 mL) and water (2 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 ml) and shaken. The resulting solid was filtered off, was washed with water and dried at reduced pressure to 0.49 g of 4-chloro-1H-benzo[d]imidazol-2-amine (yield, 49%). MS (EI): 168 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(CC(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
49.0 mg (99.0 μmol) of tert-butyl 4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)benzoate and 153 μl (1.98 mmol) of TFA were reacted according to General Method 2. Yield: 20 mg (44% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N+:24]([O-])=O)[CH:21]=3)[N:16]([CH3:27])[C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].CO>CN(C=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:27])[C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc([N+](=O)[O-])ccc3n(C)c12
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reaction time: 18 h

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxamide (250 mg) was suspended in DMF (20 ml) and methanol (10 ml) and added with raney nickel (25 mg, 10% w/w) and reduced under pressure (60 psi) for 18 hrs at room temperature. The reaction mixture was filtered through celite and DMF was evaporated to get a green solid which was washed with water to give N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide. Confirmed by ninhydrin. The compound was taken directly without purification to synthesize the following example no 54, 55, 56 and 57