Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:11])[CH3:9]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and acetyl chloride as starting materials in 58% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z=505.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(=O)=O.CC(C)=O.CS(C)=O.[C:18]([O:22][C:23](=[O:36])[N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)[C@@H:25]([CH3:28])[CH2:26][OH:27])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.O.C(N(CC)CC)C>[C:18]([O:22][C:23](=[O:36])[N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)[C@@H:25]([CH3:28])[CH:26]=[O:27])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[C@@H](CO)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](C=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
A solution of oxalyl chloride (318 mg) in methylene chloride (6 mL) was cooled using dry ice/acetone under a nitrogen atmosphere, and a solution of DMSO (258 mg) in methylene chloride (6 mL) was added. The mixture was stirred at the same temperature for 10 min, a solution of tert-butyl(3-chlorophenyl)[(1S)-2-hydroxy-1-methylethyl]carbamate (500 mg) in methylene chloride (8 mL) was added, and the mixture was stirred at the same temperature for 10 min. Triethylamine (0.925 mL) was added, and the mixture was stirred at the same temperature for 30 min. Water (30 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give the title compound as a colorless oil (yield: 480 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15](C2N=CC=CN=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].CC1(NC2N=CC(C(F)(F)F)=CN=2)CCCC1N.[N:51]1[N:52](C2C(C(O)=O)=NC=CC=2)[N:53]=[CH:54][CH:55]=1>>[CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([N:52]2[N:53]=[CH:54][CH:55]=[N:51]2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1N
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopentane-1,2-diamine (Intermediate 50; 150 mg, 0.58 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 110 mg, 0.58 mmol) and then triturated with heptane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[O:27]([CH2:26][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCOc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 80 ml of hexamethylphosphoramide and 20.1 g of β-bromophenetole is heated at 110° C. for 20 hours. The mixture is cooled, diluted with 25 ml of water, chilled, filtered and the solid washed with ethanol and with water to give crystals, mp 126°-129° C. Recrystallization from ethanol gives pale yellow crystals, mp 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]3[CH2:18][CH2:19][CH2:20][C:14]=3[N:13]([CH3:21])[C:12]2=[O:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]3[CH2:18][CH2:19][CH2:20][C:14]=3[N:13]([CH3:21])[C:12]2=[O:22])=[CH:7][C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCC2
Solvent: CC(C)(C)O
Product: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)OC(C)(C)C)c3)c1=O)CCC2

Procedure:
using 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoic acid via the corresponding acid chloride and tert.butanol there is obtained tert.butyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 189°-191° C.,
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([CH2:12][C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[Li+].[OH-]>C1COCC1>[N:1]1([C:6]2[N:11]=[N:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)Cc1ccc(-n2cnnn2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnnn2)nn1
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(6-aminopyridazin-3-yl)acetate (418 mg, 2.50 mmol) in acetic acid (10 mL) was added triethyl orthoformate (0.667 ml, 4.00 mmol), followed by sodium azide (244 mg, 3.75 mmol). The mixture was heated at 80° C. for 1 h. After cooling, the mixture was diluted with water and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (2×) and the combined organics washed with water, brine, dried (sodium sulfate) and concentrated to provide crude methyl 2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)acetate (LC-MS (IE, m/z): 193 [M+1-28]+). The crude ester was dissolved in THF (5.0 mL) and treated with 1 N LiOH (3.75 mL) and the resulting mixture was stirred for 1 h. The resulting mixture was concentrated in vacuo and the resulting powder dried under high vacuum to provide title compound which was used directly in the next step without further purification. LC-MS (IE, m/z): 173 [M+1-28]+.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11]O)[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[ClH:13]>C(O)=O.O>[Cl:13][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: Cl
Solvent: O
Solvent: O=CO
Product: O=C1O[C@H]([C@@H](O)CCl)C(O)=C1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
360 g of L-ascorbic acid in 1000 ml of formic acid are treated in a pressure vessel at 50° C with 145 g of hydrogen chloride gas in such a manner that the dosage velocity amounts to about 6.6 g per hour and the pressure amounts to about 0.4 to 0.6 atmospheres. Subsequently, the black mass obtained is evaporated at 60° C to a thick, pitch-like paste. This paste is stirred with about 2 liters of water at 60° C for 30 minutes. Subsequently, the water is evaporated off at 60° C under reduced pressure. The solid residue obtained is again dissolved in 2 liters of water, stirred at 60° C for 30 minutes and evaporated to dryness under reduced pressure at this temperature. This procedure is repeated once again. The residue is dissolved in 1.4 liters of water and extracted at room temperature 6 times with 1 liter of ethyl acetate each time. The combined ethyl acetate extracts are stirred with 20 g of active carbon for 15 minutes and subsequently filtered. The filtrate is freed from entrained water, dried over about 200 g of sodium sulfate, filtered and evaporated under reduced pressure at 40° C. The residue is dissolved in 600 ml of nitromethane at 80° C and filtered. The filter residue is back-washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are cooled to room temperature and the crystals obtained are filtered off. The crystals are dissolved at 80° C in 600 ml of nitromethane, treated with 5 g of active carbon and, after stirring for about 15 minutes at 80° C, filtered. The filter residue is washed with 100 ml of hot nitromethane (80° C). The combined nitromethane solutions are left to stand overnight at room temperature. The crystals obtained are filtered off and dissolved in 600 ml of nitromethane at about 70° C, treated with 5 g of active carbon and, after stirring for 15 minutes, filtered. The filter residue is washed with 100 ml of hot nitromethane (60° C). The combined nitromethane solutions are left to stand overnight at room temperature. The white crystals obtained are filtered off, dispersed in 100 mls of nitromethane and subsequently filtered. The thus-purified crystals are dried at 60° C under reduced pressure and further dried at 60° C for 48 hours under strongly reduced pressure (about 0.3 mmHg). There is obtained 6-chloro-6-deoxy-L-ascorbic acid of melting point 144° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].O.O[N:9]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[Cl:17].S(OC)(OC)(=O)=O>O1CCOCC1>[CH:19]1([N:9]([O:4][CH3:1])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[Cl:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(c1cccnc1Cl)N(O)C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CON(C(=O)c1cccnc1Cl)C1CCCCC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
20 parts of potassium carbonate in 25 parts of water is added to a solution of 16.9 parts of 2-chloronicotinic acid-N-hydroxy-N-cyclohexylamide in 50 parts of dioxane. At 45° C, 12.6 parts of dimethyl sulfate is dripped into the reaction solution and the whole stirred for 30 minutes at 45° C. The reaction product is precipitated by the addition of water. Crystallization from a mixture of benzene and ligroin yields 14.8 parts of 2-chloronicotinic acid-N-cyclohexyl-N-methoxyamide, m.p.: 96° to 98° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (500 mg, 1.2 mmol) in CH2Cl2 was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq., 20 mL). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) and gave the desired product (white solid, 598 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.82 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=10.8 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.50 (dd, J=13.9, 6.6 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.18 (d, J=14.5 Hz, 1H), 3.99 (m, 3H), 3.83 (s, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:20]=1>O>[C:1]([NH:15][C:13]1[CH:14]=[C:9]([Cl:8])[C:10]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:20]=2)=[C:11]([Cl:16])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(NC(C)=O)cc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
Acetic anhydride (10 mL) is treated with N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8 g), and the reaction mixture is stirred for 2 hours and left to stand overnight. It is then poured into water (100 mL), and extracted with ethyl acetate (100 mL) and then with dichloromethane (100 mL). The organic extracts are combined, dried over magnesium sulfate, and evaporated, to give N-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.4 g), m.p. 250-252° C. [Elemental analysis: C, 57.6; H, 5.05; N, 6.3; Cl, 16.1%. calculated: C, 57.5; H, 5.1; N, 6.4; Cl, 16.2%].
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[N:10]=[C:9]([CH2:11]O)[O:8][N:7]=1)[CH2:2][CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]=[C:38]1[NH:43][C:42]2[CH:44]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[S:46][C:41]=2[C:40](=[O:53])[N:39]1[CH:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[O:37]=[C:38]1[N:43]([CH2:11][C:9]2[O:8][N:7]=[C:6]([CH2:5][O:4][CH2:1][CH2:2][CH3:3])[N:10]=2)[C:42]2[CH:44]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[S:46][C:41]=2[C:40](=[O:53])[N:39]1[CH:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCCOCc1noc(CO)n1
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [3-(propoxymethyl)-1,2,4-oxadiazol-5-yl]methanol (250 mg, compound D22) and CBr4 (620 mg) in DCM (5 ml) are added triphenylphosphine (490 mg) and the reaction mixture is stirred for 15 min at RT. This solution is added to a stirred suspension of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (0.5 g; compound B50) and potassium carbonate (323 mg) in DMF and the reaction mixture is stirred for 3 h at 65° C. Afterwards the solvent is removed under vacuo, the resulting residue is treated with EtOAc/cyclohexane (1:1) and the suspension is filtered. The filtrate is purified by flash chromatography (silica gel, eluent EtOAc/cyclohexane 1:1) and the product fraction are washed with diethylether to give the title compound as a solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.COC1C=CC(B(O)O)=CC=1.Br[C:42]1[CH:43]=[C:44]([C:58]([O:60][CH3:61])=[O:59])[C:45]2[NH:46][C:47]3[CH:48]=[C:49]([O:56][CH3:57])[C:50]([Cl:55])=[CH:51][C:52]=3[C:53]=2[N:54]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:55][C:50]1[C:49]([O:56][CH3:57])=[CH:48][C:47]2[NH:46][C:45]3[C:44]([C:58]([O:60][CH3:61])=[O:59])=[CH:43][C:42]([C:16]4[CH:15]=[CH:14][C:19]([O:20][CH3:21])=[CH:18][CH:17]=4)=[N:54][C:53]=3[C:52]=2[CH:51]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OC)c(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)c(Cl)cc12
Temperature: 80 °C
Yield: 487.2 %

Procedure:
A vial containing dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (6 mg, 0.015 mmol), 4-methoxyphenylboronic acid (14 mg, 0.093 mmol), methyl 2-bromo-8-chloro-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (29 mg, 0.077 mmol), palladium(II) acetate (1.7 mg, 7.7 μmol), and potassium phosphate tribasic (49.1 mg, 0.231 mmol) was flushed with nitrogen. Tetrahydrofuran (1 mL) was added and the reaction was heated at 80° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvents removed. Radial silica gel chromatography (elution with DCM) afforded methyl 8-chloro-7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (29 mg). MS (ESI) m/z 397.0 (M+H). 1H NMR (CDCl3) δ ppm 9.31 (1H, s), 8.31 (1H, s), 8.00-8.12 (3H, m), 6.99-7.07 (2H, m), 6.90 (1H, s), 4.03 (3H, s), 3.96 (3H, s), 3.88 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH3:23])=[C:30]([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]3[N:10]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=23)[CH:29]=1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
To 5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.342 g, 1 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.256 g, 1.1 mmol) in dioxane (40 mL), was added a solution of K2CO3 (0.417 g, 3 mmol) in water (10 mL). Argon was vigorously bubbled through the mixture for 5 minutes and then tetrakis(triphenyl-phosphine)palladium(0) (0.078 g, 0.05 mmol) was added. The mixture was heated in a 95° C. oil bath for 17 hours. The solvent was pumped off in vacuo, and the residue partitioned between ethyl acetate and water. The phases separated and the organic phase washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (20 grams) eluted with 0-10% MeOH/CH2Cl2 to give the title product as a white solid. mp 122-125° C. LC-MS m/z 414 (M+H)+, 1.58 min (ret. time).
Reaction SMILES: C(OC([N:6]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH:7]1[C:8]([OH:10])=O)=O)C.C(Cl)(=O)C(Cl)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:8]([CH:7]2[C:11]([CH3:15])([CH3:16])[CH2:12][CH2:13][CH2:14][NH:6]2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: CCOC(=O)N1CCCC(C)(C)C1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)CCCNC1C(=O)N1CCCC1
Reaction time: 24 h
Yield: 54.9 %

Procedure:
To a stirred solution of 5.6 g (0.026 moles) of 1-ethoxy carbonyl-3,3-dimethyl pipecolic acid in 50 ml of methylene chloride at 0° C., under nitrogen, were added 5.0 g (0.041 moles) of oxalyl chloride. After the addition the solution was allowed to reach room temperature, stirred 24 hours and evaporated in vacuo to dryness. The crude oily residue was dissolved in 30 ml of methylene chloride and added to a stirred solution of 4.44 g (0.062 moles) of pyrrolidine in 30 ml of methylene chloride at 0° C. After the addition the solution was allowed to reach room temperature and stirring was continued overnight. This solution was washed with saturated sodium bicarbonate and then with 10% HCl. The aqueous layer was brought to basic pH with 10% NaOH and extracted twice with methylene chloride. The combined extractes were dried and evaporated in vacuo to give 3.0 g of the title compound.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][N:12]2[C:16]2[C:17]3[CH2:27][CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:18]=3[N:19]=[C:20]([NH2:22])[N:21]=2)[CH2:9]1)C1C=CC=CC=1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:10]12[CH2:15][CH:13]([N:12]([C:16]3[C:17]4[CH2:27][CH2:26][CH2:25][C:24]5[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=5[C:18]=4[N:19]=[C:20]([NH2:22])[N:21]=3)[CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: Nc1nc2c(c(N3CC4CC3CN(Cc3ccccc3)C4)n1)CCCc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Nc1nc2c(c(N3CC4CNCC3C4)n1)CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 81A (69 mg) in EtOH (1.5 mL) was treated with 20% Pd(OH)2/C (35 mg), stirred under an atmosphere of H2 for 16 hours at room temperature, then at 60° C. for 3 hours, after which the reaction was cooled, diluted with 5:1 CH2Cl2:EtOH, stirred for 20 minutes, filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.83 (d, J=11.19 Hz, 1H), 1.97-2.08 (m, 1H), 2.09-2.20 (m, 2H), 2.24-2.42 (m, 2H), 2.52 (dt, J=14.50, 5.47 Hz, 1H), 2.61-2.75 (m, 3H), 2.84-2.92 (m, 1H), 2.93-3.01 (m, 1H), 3.31-3.38 (m, 1H), 3.63 (d, J=10.17 Hz, 1H), 3.93 (dd, J=9.83, 5.43 Hz, 1H), 4.43 (dd, J=5.26, 3.56 Hz, 1H), 4.65 (s, 2H), 7.18-7.23 (m, 1H), 7.29-7.39 (m, 2H), 7.72-7.79 (m, 1H); MS (M+H)+ m/z 322.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:40][CH:41]([CH3:46])[C:42]([O:44][CH3:45])=[O:43]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:40][CH:41]([CH3:46])[C:42]([O:44][CH3:45])=[O:43])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)C(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.10 g (19.1 mmol) 5-chloro-thiophene-2-carboxylic acid are combined with 4.44 ml (40 mmol) NMM and 6.42 g (20 mmol) TBTU in 50 ml THF and then stirred for 2 hours under a nitrogen atmosphere at ambient temperature. Then 2.79 g (20 mmol) methyl 2-aminopropionate-hydrochloride and 50 ml THF are added and the mixture is stirred for a further 16 hours at ambient temperature. Then the reaction mixture is poured into water, extracted with ethyl acetate, the combined organic phases are washed with sat. sodium hydrogen carbonate solution, water, 0.5-molar hydrochloric acid, water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:30])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:19][C:18]=1[F:29])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[F:29][C:18]1[CH:19]=[C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C@H:9]1[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]1)=[O:30]
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(-n3ccc(C)n3)cc2F)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CN[C@@H](C(=O)Nc2ccc(-n3ccc(C)n3)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Boc-amine 3 (˜0.6 g, 1.427 mmol) was dissolved in 25% TFA in dichloromethane. The mixture was stirred at ambient temperature for 2 h. The solvents were removed and the residue dried under vacuum to give 4 as a tan oil (˜0.450 g).