Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]([OH:16])=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C:30]1[NH:34][N:33]=[N:32][N:31]=1>CN(C)C=O>[NH:31]1[C:30]([NH:29][C:14]([C:2]2[N:3]=[C:4]3[CH:13]=[N:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]3[CH:1]=2)=[O:16])=[N:34][N:33]=[N:32]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cn2c(cnc3ccccc32)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cn2c(cnc3ccccc32)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
A solution of 0.8 g of imidazo-[1,2-a]-quinoxaline-2-carboxylic acid, 0.7 g of carbonyldiimidazole and 40 ml of dimethylformamide was stirred at 90° C. for 30 minutes and 0.35 g of anhydrous 5-amino-tetrazole were added to the resulting clear orange solution. The mixture was stirred at 90° C. for one hour and was cooled in a refrigerator. The mixture was filtered and the recovered product was washed well with ethyl acetate and dried in vacuo to obtain 1.17 g of N-(1H-tetrazol-5-yl)-imidazo-[1,2-a]-quinoxaline-2-carboxamide which after crystallization from dimethylformamide was a white crystalline solid melting at 280°-281° C. with decomposition.
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C(OCC)C>C1(C)C=CC=CC=1.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>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:39]5[CH:44]=[N:43][CH:42]=[CH:41][N:40]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:23])([CH3:24])[CH3:25]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cnccn1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 88.1 %

Procedure:
A solution of 75 mg of 8e, 150 mg of 2-tributylstannylpyrazine and 16 mg of Pd(PPh3)4 in 2 ml of degassed toluene was heated under N2 atmosphere for 24 hr. The reaction mixture was concentrated and the crude material was chromatographed over silica gel, using a gradient of toluene/acetone. The material isolated was treated with diethyl ether and provided 66 mg of 8g; Mp 235-236° C.; MS-ESI: [M+1] 530.3;
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]([OH:30])=O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[CH:7]([N:8]([CH3:9])[C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:30])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: CNC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C(=O)CNC(=O)CCc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 2.0 mmol N-(diphenylmethyl)methylamine, 2.0 mmol (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and 6.0 mmol DIPEA in 10 ml of acetonitrile was treated with 2.2 mmol of TBTU. After 2 hours at room temperature, the reaction mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The organic phase was dried and the residue purified by chromatography (SiO2; dichloromethane/methanol) to give the title compound as a slightly yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: NCc1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 79 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and benzylamine: yield 79%.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:17]=[CH:16][C:9]([CH2:10][S:11][CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.Cl.[CH3:19][O:20][C:21](=[O:50])[C@H:22]([CH2:46][CH2:47][S:48][CH3:49])[NH:23][C:24](=[O:45])[CH2:25][N:26]([CH2:38][C@@H:39]([NH2:44])[C@@H:40]([CH3:43])[CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[CH3:19][O:20][C:21](=[O:50])[C@H:22]([CH2:46][CH2:47][S:48][CH3:49])[NH:23][C:24](=[O:45])[CH2:25][N:26]([CH2:38][C@@H:39]([NH:44][C:13](=[O:15])[CH2:12][S:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[CH:17][CH:16]=1)[C@@H:40]([CH3:43])[CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CSCc1ccc(-c2nnn[nH]2)cc1
Reactant: CC[C@H](C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CSCc1ccc(-c2nnn[nH]2)cc1

Procedure:
Following the procedure described for Example 1, Step G, [4-(1H-tetrazol-5-yl)benzylthio]acetic acid was coupled with N-(2(S)-amino-3(S)-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[CH:16])[CH:14]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:14]=1
Reactant: C#Cc1cncc(Br)c1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Add triethylamine (6.2 mL, 44 mmol), copper (I) iodide (120.3 mg, 1.10 mmol) and bis(triphenylphosphine)palladium (II) dichloride (386 mg, 0.55 mmol) to a solution of 3-bromo-5-ethynylpyridine, (prepared essentially as described in PREPARATION 23), (2.0 g, 11 mmol) and 1-iodo-3-trifluoromethylbenzene (1.53 mL, 11 mmol) in ethyl acetate (12 mL). Stir at room temperature for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate to give the title compound (2.1 g, 61%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][N:24]=[N:25][C:21]=2[CH:20]=1>C1(C)C(C)=CC=CC=1>[C:2]1([C:1]2([N:23]3[C:22]4[CH:26]=[CH:27][C:19]([Br:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: Brc1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1C
Product: O=C1OC(c2ccccc2)(n2nnc3cc(Br)ccc32)c2ccccc21

Procedure:
10.0 g (0.04 mol.) of commercial 2-benzoylbenzoic acid and 7.8 g (0.04 mol.) of 5-bromobenzotriazole were added to 300 ml of dried xylene, and refluxed for 8 hours as heat was applied thereto by means of the dehydration-reflexing apparatus. After cooling, the insoluble material was filtered off with suction, and the filtrate was concentrated to obtain 12.4 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 400 g, eluate: hexane-ethyl acetate (3:2 by volume) mixture) to obtain the intended compound, 3-phenyl-3-(5-bromo-1-benzotriazolyl)phthalide (22), in the form of white crystals. Yield 8.1 g, Melting Point 128° to 131° C.
Reaction SMILES: B(Br)(Br)Br.[C:5]12([C:15]([C:17]3[C:22]([O:23]C)=[CH:21][C:20]([O:25]C)=[CH:19][C:18]=3[Cl:27])=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.O>C(Cl)Cl>[C:5]12([C:15]([C:17]3[C:22]([OH:23])=[CH:21][C:20]([OH:25])=[CH:19][C:18]=3[Cl:27])=[O:16])[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]3)[CH2:12]1)[CH2:14]2
Reactant: COc1cc(Cl)c(C(=O)C23CC4CC(CC(C4)C2)C3)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Yield: 29.5 %

Procedure:
Boron tribromide 1M in CH2Cl2 was added to a solution of 1-adamantyl-(2-chloro-4,6-dimethoxyphenyl)methanone (7 g, 21.0 mmoles) and CH2Cl2 (30 ml). The mixture was warmed overnight and then poured into water, extracted with ethyl acetate, dried over Na2SO4 and concentrated under vacuum to give the expected product (1.9 g, 30%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared staing from 1-butyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.; MS: 451.9 (M+H)+
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH2:4][CH3:5])[CH3:3].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15]>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:6][C:2]([CH3:3])([CH3:1])[CH2:4][CH3:5])(=[O:16])=[O:15]
Reactant: CCC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Product: CCC(C)(C)NS(=O)(=O)c1ccccc1Br
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 2-methyl-2-butanamine (11.4 mL, 97.8 mmol) in dichloromethane (100 mL) was added, dropwise over a 10 min period, a solution of 2-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) in dichloromethane (ca. 50 mL). After stirring for 15 h the reaction was concentrated in vacuo. The residue was crystallized from methyl t-butyl ether to provide 10.5 g (87%) of 2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide in two crops: LCMS (neg. ion spectrum) m/z 304/306.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)/[C:7]/2=[N:16]\[OH:17])[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCC.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][O:17]/[N:16]=[C:7]1/[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:15][CH2:14][C:13]2[C:8]/1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:26]
Reactant: CCOC(=O)CCCCBr
Reactant: O/N=C1\c2ccccc2CCC1n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCO/N=C1\c2ccccc2CCC1n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+-)-(E)-2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphtalen-1-one oxime (500 mg; 2.2 mmoles) dissolved in dry DMF (27 ml) is added, under dry nitrogen atmosphere, to a pentane-washed sodium hydride suspension (160 mg NaH 55%; 3.6 mmoles), in dry DMF (10 ml). The resulting reaction mixture is stirred at r.t. for 2 hours. Then ethyl-5-bromopentanoate (0.530 ml; 3.3 mmoles) is added at r.t. and the reaction mixture is stirred at r.t. for 3 hrs., the solvent evaporated in vacuo, and the residue carefully taken up with ice-cooled water and extracted with ethyl acetate. The collected organic phases are dried over Na2SO4 and evaporated to give an oily crude material which is chromatographed over silica gel. By eluting with CH2Cl2 /MeOH (95:5), the pure title compound is obtained as a slight yellow oil (250 mg). 1H-NMR (200MH2, CDCl3) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][S:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:21]([CH2:20][S:19][CH3:18])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CSCc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CSC)cc(C(F)(F)F)c2)ncc1F

Procedure:
Intermediate 40.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(methylsulfanyl)methyl]-5-(trifluoromethyl)aniline. The residue was purified by chromatography (hexane to hexane/ethyl acetate 15%) to give the desired product.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][C:7]([C:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[N:20]([CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:22][N:23]=3)[CH2:14]2)=[O:11])=[N:8][CH:9]=1)[CH3:3]>CO.[Pd]>[CH:2]([C:4]1[CH:9]=[N:8][C:7]([C:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[N:20]([CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:22][N:23]=3)[CH2:14]2)=[O:11])=[N:6][CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a solution of (S)-5-(prop-1-en-2-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.090 g, 0.26 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.027 g, 0.03 mmol, 0.1 eq). The reaction mixture was equipped with a H2 balloon and stirred for 1 hr at room temperature. The contents were filtered and the purified by HPLC to afford (S)-5-isopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.048 g, 0.14 mmol, 53%). 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 2 H), 7.76 (s, 1 H), 7.71 (d, J=5.8 Hz, 1 H), 7.55 (s, 1 H), 6.92 (s, 1 H), 6.84 (d, J=5.9 Hz, 1 H), 5.00-3.60 (br, 5 H), 3.18-3.00 (m, 1 H), 2.65-2.30 (br, 2 H), 1.36 (d, J=7.0 Hz, 6 H); MS: (ES) m/z calculated for C19H22N6O [M+H]+ 351.2, found 351.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:24]=[CH:23][C:15]3[O:16][C:17]([CH3:22])([CH3:21])[C:18](=[O:20])[NH:19][C:14]=3[CH:13]=2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[N:31][NH:32]2)=[CH:28][CH:27]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([NH:25][C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:24]=[CH:23][C:15]5[O:16][C:17]([CH3:22])([CH3:21])[C:18](=[O:20])[NH:19][C:14]=5[CH:13]=4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:34]=2)[CH:30]=[N:31]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)nc4[nH]ccc34)cc2NC1=O
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC1(C)Oc2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)nc4[nH]ccc34)cc2NC1=O
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To a mixture of 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.050 g) inn-butyl alcohol (0.6 mL) was added 6-aminoindazole (0.028 g) and trimethylsilyl chloride (TMSCl) (0.013 mL). After heating at 115° C. for 15 h, the mixture was purified by preparative HPLC to give 6-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.004 g, MS [MH] 441.1) (Compound 16-1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:31][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1oc(-c2ccc(-c3cccc(C#N)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-cyanobenzene boronic acid (219 mg, 1.49 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (100 mg, 0.30 mmol) to give 21 mg (20%). MS (m/e) 358.2 (M+1)
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[H][H]>CO.[Pd]>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-[n+]2ccc(C(N)=O)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COc1cccc(N2CCC(C(N)=O)CC2)c1
Yield: 82.6 %

Procedure:
A suspension of 4-carbamoyl-1-(3-methoxyphenyl)-pyridinium chloride (26 g) in methanol (300 ml) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium-on-carbon catalyst (2.0 g) until hydrogen uptake ceased (~2 days) The mixture was filtered, excess triethylamine added and the solvent removed in vacuo to give a pink solid. This was partitioned between water and chloroform. The organic phase was dried and the solvent removed in vacuo to give 1-(3-methoxyphenyl)piperidine-4-carboxamide as a pink solid (19 g), m.p. 153°-156° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH2:10][CH2:11][OH:12])=[CH2:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CCO.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C(CCO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(CCO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(4-hydroxybut-1-en-2-yl)phenyl)carbamate (272 mg, 0.843 mmol) was taken up in EtOH (8 mL) and the flask was evacuated and filled with N2 3×. Next, platinum (IV) oxide (19.14 mg, 0.084 mmol) was added, and the flask was purged again. The reaction was stirred under 1 atm hydrogen at room temperature for 3 h. The reaction was monitored by TLC. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-40% EtOAc/Hex; 40 g column). Tert-butyl (2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)carbamate (161 mg) was obtained as a colorless glassy liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=O)[CH2:7][CH2:6]2.Cl.[CH2:17]([O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CO>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)CC(Nc1ccc(OCc3ccccc3)cc1)CC2
Reaction time: 3.5 h
Yield: 90 %

Procedure:
A solution of 500 mg (2.42 mmol, Aldrich) of 6,7-dimethoxy-2-tetralone and 570 mg (2.42 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride in 20 ml of MeOH was stirred over 3A molecular sieves at 25° C., then 76 mg (1.21 mmol, Aldrich) of NaBH3CN were added. This mixture was stirred for 3.5 hours, filtered and then saturated NaHCO3 was added to the filtrate. This solution was extracted with EtOAc twice, the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 8, 1:5 then 1:3 EtOAc/petroleum ether) afforded mg (90%) of title compound as a pale pink solid:m.p. 85°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc2c(cc1Br)NCC2
Reactant: O=C=Nc1cccnc1
Product: CSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 71 %

Procedure:
6-Bromo-5-methylthioindoline (D85) (0.26 g, 1.06 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol to afford the title compound (0.27 g, 71%) as a white crystalline solid m.p. 242°-244° C.
Reaction SMILES: C(COC1C2CC(=CCCN3CCC(C4C=CC(Cl)=CC=4)(O)CC3)C3[C:15](OC=2C=CC=1)=[N:16][CH:17]=CC=3)(O)=O.[C:38]([C:41]1[C:46]2[CH2:47][C:48](=[CH:56][CH2:57][CH2:58][N:59]3[CH2:64][CH2:63][C:62]([C:66]4[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=4)([OH:65])[CH2:61][CH2:60]3)[C:49]3[C:50]([O:55][C:45]=2[CH:44]=[CH:43][CH:42]=1)=[N:51][CH:52]=[CH:53][CH:54]=3)(O)=[O:39]>>[Cl:72][C:69]1[CH:68]=[CH:67][C:66]([C:62]2([OH:65])[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH:56]=[C:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[O:55][C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([C:38]([N:16]([CH3:17])[CH3:15])=[O:39])[C:46]=4[CH2:47]3)[CH2:64][CH2:63]2)=[CH:71][CH:70]=1
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: O=C(O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: CN(C)C(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 118.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)N(c1ccccc1)c1ccccc1

Procedure:
Employing the general method of Example 1, 27.5 g (0.12 mol) of diphenylcarbamic chloride and 20 g (0.12 mol) of 4-aminopyridine were heated under reflux for two hours in 150 ml of chloroform containing 12.0 g (0.12 mol) of triethylamine to produce the title compound as a pale yellow solid.