Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[N:22][C:23]#[N:24])SC)[N:8]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:29][CH3:28])=[N:22][C:23]#[N:24])[N:8]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CNC(=NC#N)NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butylthio]pyrimidine (0.17 g.) in 33% w/v methylamine in ethanol was left at room temperature for 18 hours and then evaporated to dryness. The residue was triturated with ether and the insoluble solid collected and recrystallised from ethyl acetate to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(2-cyano-3-methylguanidino)butylthio]pyrimidine, m.p. 179°-180°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:14]([NH2:17])(=[S:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:14]1[S:16][CH:12]=[C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=2)[N:17]=1
Reactant: CC(N)=S
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Br)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 80 %

Procedure:
A solution of 3-bromo-(4-nitrophenyl)-ethanone (2.5 mmol) and thioacetamide (3 mmol) in N,N-dimethylformamide (20 mL) was heated at 65° C. for 8 h. Ethyl acetate (40 mL) was added and the solution was washed with water (3×20 mL). The product was purified by crystallization from ether to give the title product (80%). ESMS [M+H]+: 221.2
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])(O)=[O:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:7]([C:6]1[S:5][CH2:4][C:1](=[O:2])[N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]=12)#[N:8]
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCC(=O)O)=NCC2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1=C(C#N)SCC(=O)N1CC2
Reaction time: 48 h

Procedure:
To 3.2 g. of α-(carboxymethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 15 ml. of pyridine and 15 ml. of acetic anhydride are added. The solution is allowed to stand at room temperature for two days. 2.8 g. of 1-Cyano-9,10-dimethoxy-3,4,6,7-tetrahydro-1,4-thiazino[3,4-a]isoquinoline-4-one are obtained in a crystalline form. The product is identical with the product of Example 24.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=C(CCl)N1CCOCC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available 2-chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][CH:18]=1
Reactant: Oc1cncc(Br)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cncc(Br)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5-bromopyridin-3-ol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Temperature: 150 °C
Yield: 67.5 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2 g, 10 mmol), 3,6-dichloropyridazine (1.79 g, 12 mmol) and TEA (2.1 ml, 15 mmol) was dissolved in dry DMF (30 ml) and the reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (300 ml). The organic phase was dried (Na2SO4), filtrated and evaporated. The residue was purified by silica gel column chromatography using a 98:2 mixture of DCM:MeOH to give the title compound (2.11 g, 68%) as a solid. 1H-NMR (CDCl3, 500 MHz): δ 7.19 (d, 1H), 6.91 (d, 1H), 4.48 (bs, 1H), 4.29-4.20 (m, 2H), 3.73 (bs, 1H), 3.14-3.04 (m, 2H), 2.10-2.02 (m, 2H), 1.49-1.38 (m, 2H), 1.45 (s, 9H); 13C-NMR (CDCl3, 125 MHz): δ 158.9, 155.2, 146.7, 128.9, 115.5, 79.6, 47.9, 44.4, 31.9, 28.5.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][C:21](=[CH2:26])[C:22]([O:24][CH3:25])=[O:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:26][C:21](=[CH2:20])[C:22]([O:24][CH3:25])=[O:23])[CH2:3][C:2]([F:17])([F:18])[F:1])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: C=C(CBr)C(=O)OC
Product: C=C(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Synthesized as described in example 2 from 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and methyl 2-(bromomethyl)acrylate: MS (ES) m/z 367 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=[O:8])[CH3:2].ClC1C=C(C=C(Cl)N=1)C(O)=[O:21].N1CCOCC1>>[CH3:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N:3]2[CH2:1][CH2:2][O:21][CH2:15][CH2:14]2)[N:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Solvent: C1COCCN1
Product: Cc1cc(C(=O)O)cc(N2CCOCC2)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid starting from 2,6-dichloro-isonicotinic acid and morpholine; LC-MS: tR=0.47 min, [M+1]+=223.08.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>CN(C=O)C.[Mn]>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Agent: [Mn]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (305 mg, 1.03 mmol) in DMF, manganese (113 mg, 2.06 mmol), NiBr2bipy (27 mg, 0.07 mmol), ethyl-2-chloro propionate (0.17 mL, 1.34 mmol) was added, followed by addition of TFA (0.002 mL, 0.028 mmol). The mixture was stirred for 1 day at 65° C. The reaction mixture was quenched by conc. HCl (7-drops) and then extracted with diethyl ether, dried (MgSO4) and the solvent was evaporated in vacuo. The residue was purified by CC (EtOAc/n-hexane). 2-(4-(ethyl-sulfonamidomethyl)-3-fluorophenyl)propanoic acid in pure form (65 mg, 20%) was obtained.
Reaction SMILES: C([O-])(O)=O.[Na+].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]=2[CH:19]=1)([O-:8])=[O:7].Br[CH2:21][CH2:22][F:23]>O>[F:23][CH2:22][CH2:21][N:16]1[C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][C:13]=2[CH2:14][S:15]1(=[O:18])=[O:17]
Reactant: FCCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2CCF
Temperature: 80 °C
Yield: 66.9 %

Procedure:
NaHCO3 (0.93 g, 11.0 mmol) is dissolved in H2O (15 mL) and 5-Nitro-1,3-dihydro-2H-2,1-benzisothiazole-2,2-dione (1) (1.90 g, 8.9 mmol) is added with stirring. The mixture is heated to 80° C. for 0.5 hrs and a yellow solid formed. The mixture is cooled to 0° C. and filtered. The solid is washed with cold H2O (15 mL) then with cold EtOH (25 mL). The yellow solid thus obtained is dried under high vacuum then dissolved in dry DMF (15 mL). 1-Bromo-2-fluoroethane (1.52 mL, 20.0 mmol) is added and the solution heated to 100° C. for 4 hrs. The solution is cooled to room temperature then poured into ice water (50 mL). The solid is collected by filtration and gave crystals (1.55 g, 67%) after recrystallization from EtOH. Mp 142-4° C. HRMS (FAB) calcd for C9H9FN2O4S +NA1 283.0165, found 283.0166.
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:27])[C@H:5]2[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:27])[C@H:5]1[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 84.1 %

Procedure:
A solution of (6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one (200 mg) in a mixture of acetic acid (3.2 ml) and water (0.8 ml) was heated at 65° C. for 1 hour. The mixture was cooled to room temperature and evaporated in vacuo. The crystalline residue was washed with ether to give (3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one (151 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[C:3]([OH:5])=[O:4].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1.[OH-].[Na+]>[NH2:10][C:8]([NH:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH:1][C:12]([O:14][CH3:15])=[O:13])=[O:9]
Reactant: COC(=O)Cl
Reactant: NC(=O)NCC(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](CNC(N)=O)C(=O)O
Temperature: 60 °C
Reaction time: 7 h
Yield: 53.6 %

Procedure:
A solution of 2-amino-3-ureido-propionic acid (0.147 g, 1.0 mmol) in 1,4-dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methyl chloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, and extracted with dichloromethane. The aqueous phase was acidified to pH 7 with 1 N HCl and evaporated to dryness. The resulting solid was trituated with 3:1 dichloromethane/isopropanol, filtered, and the filtrate was concentrated to yield a white solid (0.11 g, 53.6%) which was used for the next step without further purification.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([N:25]4[CH2:28][CH:27]([S:29][C:30]5[C@H:31]([CH3:54])[C@@H:32]6[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]6[C:34]=5[C:35]([O:37]CC5C=CC([N+]([O-])=O)=CC=5)=[O:36])[CH2:26]4)[S:23][CH:24]=3)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([N:25]3[CH2:28][CH:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([OH:37])=[O:36])[CH2:26]3)[S:23][CH:24]=2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N[C@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)cs4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N[C@H]5CCNC5)cs4)C3)[C@H](C)[C@H]12
Reaction time: 4.5 h
Yield: 37.8 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (390 mg, 0.483 mmol) (obtained as described in Example 57(1)) in a mixture of tetrahydrofuran (20 ml) and distilled water (20 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (390 mg) at room temperature for 4.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The mixture was shaken in a separatory funnel. The aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→distilled water:acetonitrile (76:24)) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-((3S)-pyrrolidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (90 mg, yield 38%) as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13]([C:15]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45])[CH:39]=O>O1CCCC1>[C:8]([O:12][C:13](=[O:14])/[CH:15]=[CH:39]/[C:38]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:36]([F:35])[CH:37]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)c1ccccc1[P+](C)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Potassium tert-butylate (0.438 g, 3.9 mmol) was added to a suspension of tert-butoxy carbonyl methyl triphenyl phosphonium bromide (1.61 g, 3.9 mmol; CAS Reg. No. 35000-37-4) in tetrahydrofuran (10 ml). The suspension was stirred for 15 min at ambient temperature. 3-Fluoro-4-nitrobenzaldehyde (600 mg, 3.5 mmol; CAS Reg. No. 160538-51-2) was added, the mixture was stirred for 1.5 h at ambient temperature, poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. The solid was filtered off and the filtrate was concentrated under reduced pressure to give a brown oil which was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:methyl tert-butyl ether (100:0 to 80:20 v/v) to afford the title compound as a brown oil (812 mg, 3.04 mmol; 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:15](=O)[CH3:16])[CH:3]=1.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:14][C:15]([CH3:16])=[C:13]1[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]1
Reactant: CC(=O)Nc1cc(Cl)ccc1-c1ccccc1
Agent: N
Product: Cc1nc2cc(Cl)ccc2c2ccccc12
Temperature: 120 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
N-(4-Chloro-1,1′-biphenyl-2-yl)acetamide (2.65 g, 10.8 mmol) was mixed with polyphosphoric acid (50 g) and heated to 120° C. with vigorous stirring for 12 hours. The hot reaction mixture was poured into a beaker containing ice and stirred vigorously until homogeneous. The solution was neutralized to a pH>8 with concentrated aqueous ammonia. A white precipitate formed and was filtered. The white solid was dissolved in ethyl acetate (250 mL) and re-filtered. The filtrate was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent concentrated in vacuo to a brown solid. The brown solid was purified by trituration with ethyl acetate/hexane to afford the title compound as white crystals (2.28 g, 93%), m.p. 129-131° C.;
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:32])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:13]([C:33]([OH:35])=[O:34])[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C.C(O)CCC.C(OCC)(=O)C.O>Br.C(O)(=O)C>[Br:31][C:27]1[CH:26]=[C:25]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]2[C:33]([OH:35])=[O:34])=[O:32])[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1cccc(Br)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.13 g (3.96 mmole) portion of (S)-4-(benzyloxycarbonyl)-1-[N-(3-bromophenyl-N-phenylcarbamoyl]piperazine-2-carboxylic acid (from Step B) was dissolved in 40 ml of 30% HBr in acetic acid. After stirring for 1 hour at 25° C., the solution was flushed with nitrogen to remove the excess of HBr. Concentration in vacuo gave an oily residue which was partitioned between 100 ml of methylene chloride and 100 ml of water. The stirred slurry was neutralized to pH 7 with 10% NaOH solution. After a brief stirring the entire mixture was filtered to collect 1.50 g (3.71 mmole, 94%) of white solid which was homogeneous by TLC (5:1:1:1 ethyl acetate-n-butyl alcohol-ethyl acetate-water Rf =0.33).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C(#N)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c(N)cnc2ccccc12
Reaction time: 20 h
Yield: 100.3 %

Procedure:
tert-Butyl (2S)-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate (5.04 g, 14.5 mmol) was dissolved in acetonitrile (300 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 1.03 g) was then added and the reaction mixture was shaken under H2 at 30 PSI (2.1×105 Pa). After 20 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give tert-butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]propylcarbamate (4.60 g) as an orange foam.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:2].[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([Br:28])=[CH:22][CH:23]=3)[C:18](=[O:29])[C:17]=2[CH:16]=1.OO.NC(N)=O>ClCCl>[Br:28][C:21]1[CH:20]=[C:19]2[C:24]([C:25]3[CH:26]=[CH:27][C:15]([Br:14])=[CH:16][C:17]=3[C:18](=[O:29])[O:2]2)=[CH:23][CH:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: O=c1oc2cc(Br)ccc2c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 134.5 %

Procedure:
A solution of TFAA (2.1 mL, 3.15 mmol) in dichloromethane (5 mL) was added dropwise to a suspension of 2,7-dibromo-fluoren-9-one (3.3 g, 10 mmol) and H2O2-urea (1.4 g, 15 mL) in dichloromethane (50 mL). The mixture was stirred at room temperature for 48 hours, a second portion of H2O2-urea was added, and stirring was continued at room temperature for a further 72 hours. The mixture was filtered, the organic phase was extracted with water (50 mL), and dried over Na2SO4. After removal of solvent, the residue was heated with 2N NaOH at 80° C. for 10 minutes, filtered, the cooled filtrate extracted with ether. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (200 mL). HCl (2 mL 4M solution) was added to the ethyl acetate and heated for 2 hours. The solvent was removed under vacuum, the residue was recrystallized from ethyl acetate/ethanol to give the final product 3,8-Dibromo-benzo[c]chromen-6-one as a white solid (1.5 g, 40%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3][CH:2]=1.Cl>CO>[N:22]1([C:20]2[N:21]=[C:16]([N:15]3[C:9]4[CH:8]=[C:7]([C:5]5[CH:4]=[N:3][CH:2]=[N:1][CH:6]=5)[N:12]=[CH:11][C:10]=4[CH:13]=[N:14]3)[CH:17]=[CH:18][CH:19]=2)[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cncnc5)cc43)n2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cncnc4)cc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A suspension of tert-butyl 4-(6-(6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (320 mg, 0.68 mmol) in a solution of HCl in MeOH (3.0 N, 20 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepared HPLC to afford 175 as a light yellow solid (220 mg, yield 87%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.43 (s, 1H), 9.39 (s, 1H), 9.35 (d, J=3.0 Hz, 1H), 9.28 (d, J=3.0 Hz, 1H), 9.06 (d, J=11.5 Hz, 1H), 8.66 (d, J=5.5 Hz, 1H), 7.70 (dd, J=8.0 and 16.5 Hz, 1H), 7.17 (dd, J=7.5 and 11.0 Hz, 1H), 6.61 (t, J=8.0 Hz, 1H), 3.83 (s, 2H), 3.77 (s, 2H), 3.56 (m, 1H), 2.95 (t, J=5.0 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 1.84 (t, J=5.0 Hz, 2H). ESI (MS) m/z: 373 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].[Na+].Cl[C:16]([F:21])([F:20])C([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(#N)C>[F:20][CH:16]([F:21])[O:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13]
Reactant: CCOC(=O)c1ncnc(O)c1C
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ncnc(OC(F)F)c1C
Temperature: 90 °C

Procedure:
In a round bottom flask (5 litre) was taken Ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate 40 (85 g, 466 mmol), chlorodifluoroacetic acid sodium salt (106.7 g, 699 mmol), sodium carbonate (98.9 g, 933 mmol), acetonitrile (1500 ml) and DMF (425 ml). The reaction mixture was heated to 90° C. for 16 h. The Progress of the reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and then neutralized with saturated ammonium chloride. The solvent was removed under vacuum and extracted with ethyl acetate. The combined organic layer was washed with water, brine and concentrated under reduced pressure. The crude compound was purified through silica gel chromatography eluting (3-4% ethyl acetate) to afford ethyl 6-(difluoromethoxy)-5-methylpyrimidine-4-carboxylate 48b as a pale yellow liquid. Yield: 14 g (13%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:13]
Reactant: Nc1sc2ccccc2c1C(=O)O
Reactant: O=C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1sc2ccccc2c1C(=O)N1CCC(=O)CC1
Yield: 84 %

Procedure:
A solution of 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 g, 1.0 equivalent) and 4-piperidone (1.0 equivalent) in DMF (0.33 M) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and volatiles removed under reduced pressure. Residue was purified by SiO2 chromatography (5%-10% MeOH/CH2Cl2 gradient) to afford the 1-(2-aminobenzo[b]thiophene-3-carbonyl)piperidin-4-one (6A, 84%).